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19 pages, 3377 KiB

Open AccessCommunication

Antiproliferative Activity of a New Quinazolin-4(3H)-One Derivative via Targeting Aurora Kinase A in Non-Small Cell Lung Cancer

by Ji Yun Lee, Huarong Yang, Donghwa Kim, Kay Zin Kyaw, Ruoci Hu, Yanhua Fan and Sang Kook Lee

Pharmaceuticals 2022, 15(6), 698; https://doi.org/10.3390/ph15060698 - 2 Jun 2022

Cited by 4 | Viewed by 2439

Abstract

Non-small cell lung cancer (NSCLC) is the most common lung cancer subtype. Although chemotherapy and targeted therapy are used for the treatment of patients with NSCLC, the survival rate remains very low. Recent findings suggested that aurora kinase A (AKA), a cell cycle [...] Read more.

Non-small cell lung cancer (NSCLC) is the most common lung cancer subtype. Although chemotherapy and targeted therapy are used for the treatment of patients with NSCLC, the survival rate remains very low. Recent findings suggested that aurora kinase A (AKA), a cell cycle regulator, is a potential target for NSCLC therapy. Previously, we reported that a chemical entity of quinazolin-4(3H)-one represents a new template for AKA inhibitors, with antiproliferative activity against cancer cells. A quinazolin-4(3H)-one derivative was further designed and synthesized in order to improve the pharmacokinetic properties and antiproliferation activity against NSCLC cell lines. The derivative, BIQO-19 (Ethyl 6-(4-oxo-3-(pyrimidin-2-ylmethyl)-3,4-dihydroquinazolin-6-yl)imidazo [1,2-a]pyridine-2-carboxylate), exhibited improved solubility and antiproliferative activity in NSCLC cells, including epidermal growth factor receptor–tyrosine kinase inhibitor (EGFR-TKI)-resistant NSCLC cells. BIQO-19 effectively inhibited the growth of the EGFR-TKI-resistant H1975 NSCLC cells, with the suppression of activated AKA (p-AKA) expression in these cells. The inhibition of AKA by BIQO-19 significantly induced G₂/M phase arrest and subsequently evoked apoptosis in H1975 cells. In addition, the combination of gefitinib and BIQO-19 exhibited synergistic antiproliferative activity in NSCLC cells. These findings suggest the potential of BIQO-19 as a novel therapeutic agent for restoring the sensitivity of gefitinib in EGFR-TKI-resistant NSCLC cells. Full article

(This article belongs to the Special Issue Protein Kinases and Cancer)

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19 pages, 11816 KiB

Open AccessArticle

Artonin F Induces the Ubiquitin-Proteasomal Degradation of c-Met and Decreases Akt-mTOR Signaling

by Rapeepun Soonnarong, Ismail Dwi Putra, Nicharat Sriratanasak, Boonchoo Sritularak and Pithi Chanvorachote

Pharmaceuticals 2022, 15(5), 633; https://doi.org/10.3390/ph15050633 - 21 May 2022

Cited by 4 | Viewed by 2500

Abstract

Targeted therapies that selectively inhibit certain molecules in cancer cells have been considered promising for cancer treatment. In lung cancer, evidence has suggested that mesenchymal-epithelial transition factor (c-Met) oncoprotein drives cancer progression through its signaling transduction pathway. In this paper, we report the [...] Read more.

Targeted therapies that selectively inhibit certain molecules in cancer cells have been considered promising for cancer treatment. In lung cancer, evidence has suggested that mesenchymal-epithelial transition factor (c-Met) oncoprotein drives cancer progression through its signaling transduction pathway. In this paper, we report the downregulation of c-Met by artonin F, a flavonoid isolated from Artocarpus gomezianus. Artonin F was found to be dominantly toxic to lung cancer cells by mediating apoptosis. With regard to its mechanism of action, artonin F downregulated c-Met expression, consequently suppressed the phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin signaling, increased Bax expression, decreased Bcl-2 expression, and activated caspase-3. The depletion of c-Met was mediated by ubiquitin-proteasomal degradation following co-treatment with artonin F, with the proteasome inhibitor MG132 reversing its c-Met-targeting effect. The immunoprecipitation analysis revealed that artonin F significantly promoted the formation of the c-Met–ubiquitin complex. Given that ubiquitin-specific protease 8 (USP8) prevents c-Met degradation by deubiquitination, we performed a preliminary in silico molecular docking and observed that artonin F blocked the catalytic site of USP8. In addition, artonin F interacted with the catalytic residues of palmitoylating enzymes. By acting as a competitive inhibitor, artonin F could reduce the degree of palmitoylation of c-Met, which affected its stability and activity. In conclusion, c-Met is critical for cancer cell survival and the failure of chemotherapeutic regimens. This novel information on the c-Met downregulating effect of artonin F will be beneficial for the development of efficient anticancer strategies or targeted therapies. Full article

(This article belongs to the Special Issue Protein Kinases and Cancer)

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14 pages, 2831 KiB

Open AccessArticle

Cyclin-Dependent Kinase and Antioxidant Gene Expression in Cancers with Poor Therapeutic Response

by George S. Scaria, Betsy T. Kren and Mark A. Klein

Pharmaceuticals 2020, 13(2), 26; https://doi.org/10.3390/ph13020026 - 5 Feb 2020

Cited by 1 | Viewed by 2848

Abstract

Pancreatic cancer, hepatocellular carcinoma (HCC), and mesothelioma are treatment-refractory cancers, and patients afflicted with these cancers generally have a very poor prognosis. The genomics of these tumors were analyzed as part of The Cancer Genome Atlas (TCGA) project. However, these analyses are an [...] Read more.

Pancreatic cancer, hepatocellular carcinoma (HCC), and mesothelioma are treatment-refractory cancers, and patients afflicted with these cancers generally have a very poor prognosis. The genomics of these tumors were analyzed as part of The Cancer Genome Atlas (TCGA) project. However, these analyses are an overview and may miss pathway interactions that could be exploited for therapeutic targeting. In this study, the TCGA Pan-Cancer datasets were queried via cBioPortal for correlations among mRNA expression of key genes in the cell cycle and mitochondrial (mt) antioxidant defense pathways. Here we describe these correlations. The results support further evaluation to develop combination treatment strategies that target these two critical pathways in pancreatic cancer, hepatocellular carcinoma, and mesothelioma. Full article

(This article belongs to the Special Issue Protein Kinases and Cancer)

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11 pages, 2533 KiB

Open AccessArticle

Prostate-Derived ETS Factor (PDEF) Modulates Yes Associated Protein 1 (YAP1) in Prostate Cancer Cells: A Potential Cross-Talk between PDEF and Hippo Signaling

by Praveen Kumar Jaiswal, Suman Mohajan, Sweaty Koul, Fengtian Wang, Runhua Shi and Hari K. Koul

Pharmaceuticals 2019, 12(4), 181; https://doi.org/10.3390/ph12040181 - 10 Dec 2019

Cited by 4 | Viewed by 4050

Abstract

PDEF (prostate-derived ETS factor, also known as SAM-pointed domain containing ETS transcription factor (SPDEF)) is expressed in luminal epithelial cells of the prostate gland and associates with luminal phenotype. The Hippo pathway regulates cell growth/proliferation, cellular homeostasis, and organ development by modulating phosphorylation [...] Read more.

PDEF (prostate-derived ETS factor, also known as SAM-pointed domain containing ETS transcription factor (SPDEF)) is expressed in luminal epithelial cells of the prostate gland and associates with luminal phenotype. The Hippo pathway regulates cell growth/proliferation, cellular homeostasis, and organ development by modulating phosphorylation of its downstream effectors. In previous studies, we observed decreased levels of PDEF during prostate cancer progression. In the present study, we evaluated the effects of the expression of PDEF on total/phosphoprotein levels of YAP1 (a downstream effector of the Hippo pathway). We observed that the PC3 and DU145 cells transfected with PDEF (PDEF-PC3 and PDEF-DU145) showed an increased phospho-YAP1 (Ser127) and total YAP1 levels as compared to the respective PC3 vector control (VC-PC3) and DU145 vector control cells (VC-DU145). We also observed an increased cytoplasmic YAP1 levels in PDEF-PC3 cells as compared to VC-PC3 cells. Moreover, our gene set enrichment analysis (GSEA) of mRNA expression in PDEF-PC3 and VC-PC3 cells revealed that PDEF resulted in inhibition of YAP1 target genes, directly demonstrating that PDEF plays a critical role in modulating YAP1 activity, and by extension in the regulation of the Hippo pathway. We also observed a decrease in YAP1 mRNA levels in prostate cancer tissues as compared to normal prostate tissues. Our analysis of multiple publicly available clinical cohorts revealed a gradual decrease in YAP1 mRNA expression during prostate cancer progression and metastasis. This decrease was similar to the decrease in PDEF levels, which we had reported earlier, and we observed a direct correlation between PDEF and YAP1 expression in CRPC data set. To the best of our knowledge, these results provide the first demonstration of inhibiting YAP1 activity by PDEF in any system and suggest a cross-talk between PDEF and the Hippo signaling pathway. Full article

(This article belongs to the Special Issue Protein Kinases and Cancer)

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Effect of prostate-derived ETS factor (PDEF) on YAP1 and Phospho-YAP1 Protein (Ser127) protein levels and YAP1 transcriptional activity in prostate cancer cells in culture. (A) PDEF-PC3 cells have a higher amount of phospho-YAP1 protein and total YAP1 protein as compared to VC-PC3 cells. (B) PDEF-DU145 cells have a higher amount of phospho-YAP1 protein and total YAP1 protein as compared to VC-DU145 cells. The adjacent graph is quantitation of western blots ratio of phospho (Ser127)/phospho/total YAP1 protein level. (C) PDEF-PC3 cells showed more cytoplasmic distribution of YAP1 protein, while VC-PC3 cells showed more nuclear localization of YAP1 protein (scale bar 20 µm). (D) Gene set enrichment analysis (GSEA) of the YAP conserved gene signature in VC-PC3 and PDEF-PC3 cells. Full article ">Figure 2
YAP1 mRNA expression in multiple PCa clinical cohorts. YAP1 mRNA data were analyzed from The Cancer Genome Atlas (TCGA) datasets through UALCAN and the c-Bioportal web server. (A) mRNA level of YAP1 was significantly decreased in primary prostate tumors as compared to normal prostate tissues. (B) A decrease in YAP1 mRNA levels was observed in patients with a higher Gleason score (TCGA datasets) as compared to normal controls. (C) YAP1 mRNA levels were significantly decreased in PCa patients irrespective of lymph node metastasis as compared to normal controls (TCGA datasets). (D) 51% of patients showed a genetic alteration in YAP1 mRNA levels in the Prostate Adenocarcinoma MSKCC dataset. [<a href="#B31-pharmaceuticals-12-00181" class="html-bibr">31</a>] (E) Representative images is from The Human Protein Atlas showed a decreased level of YAP1 protein in high-grade PCa tumor samples as compared to low-grade PCa tumor samples. Full article ">Figure 3
PDEF and YAP1 mRNA levels in CRPC/NEPC patients. (A) YAP1 and PDEF mRNA levels were significantly decreased in NEPC patients as compared to CRPC patients (CRPC/NEPC dataset). [<a href="#B33-pharmaceuticals-12-00181" class="html-bibr">33</a>] (B) A significant positive correlation was observed between YAP1 and PDEF mRNA in the CRPC/NEPC dataset. Full article ">Figure 4
Proposed model for modulations of Hippo pathway by PDEF. Our results show that PDEF increases expression and phosphorylation (Ser127) of YAP1 in prostate cancer cells. We hypothesize that PDEF might regulate YAP1 phosphorylation indirectly by modulating expression and or activities of various components of the Hippo pathway as shown. PDEF overexpression inhibits the YAP1 conserved gene signature. Dashed red lines indicate hypothetical links, while solid black lines indicate currently established pathways. The solid red line link was established for the first time in the present study. Full article ">

22 pages, 3119 KiB

Open AccessArticle

CK2 Pro-Survival Role in Prostate Cancer Is Mediated via Maintenance and Promotion of Androgen Receptor and NFκB p65 Expression

by Janeen H. Trembley, Betsy T. Kren, Md. J. Abedin, Daniel P. Shaughnessy, Yingming Li, Scott M. Dehm and Khalil Ahmed

Pharmaceuticals 2019, 12(2), 89; https://doi.org/10.3390/ph12020089 - 14 Jun 2019

Cited by 12 | Viewed by 4550

Abstract

The prosurvival protein kinase CK2, androgen receptor (AR), and nuclear factor kappa B (NFκB) interact in the function of prostate cells, and there is evidence of crosstalk between these signals in the pathobiology of prostate cancer (PCa). As CK2 is elevated in PCa, [...] Read more.

The prosurvival protein kinase CK2, androgen receptor (AR), and nuclear factor kappa B (NFκB) interact in the function of prostate cells, and there is evidence of crosstalk between these signals in the pathobiology of prostate cancer (PCa). As CK2 is elevated in PCa, and AR and NFκB are involved in the development and progression of prostate cancer, we investigated their interaction in benign and malignant prostate cells in the presence of altered CK2 expression. Our results show that elevation of CK2 levels caused increased levels of AR and NFκB p65 in prostate cells of different phenotypes. Analysis of TCGA PCa data indicated that AR and CK2α RNA expression are strongly correlated. Small molecule inhibition or molecular down-regulation of CK2 caused reduction in AR mRNA expression and protein levels in PCa cells and in orthotopic xenograft tumors by various pathways. Among these, regulation of AR protein stability plays a unifying role in CK2 maintenance of AR protein levels. Our results show induction of various endoplasmic reticulum stress signals after CK2 inhibition, which may play a role in the PCa cell death response. Of note, CK2 inhibition caused loss of cell viability in both parental and enzalutamide-resistant castrate-resistant PCa cells. The present work elucidates the specific link of CK2 to the pathogenesis of PCa in association with AR and NFκB expression; further, the observation that inhibition of CK2 can exert a growth inhibitory effect on therapy-resistant PCa cells emphasizes the potential utility of CK2 inhibition in patients who are on enzalutamide treatment for advanced cancer. Full article

(This article belongs to the Special Issue Protein Kinases and Cancer)

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Effects of increased CK2α expression on AR and NFκB p65 protein levels. (A) Immunoblot analysis of RWPE-1 cells stably expressing Flag-CK2α after 45, 62 and 73 days in culture. Control lanes represent either parental RWPE-1 cells or RWPE-1 cells stably expressing empty vector collected simultaneously with Flag-CK2α cells. Proteins detected are indicated on the right side of the blots. Actin signal was used as the loading control. (B) Immunoblot analysis of RWPE-1 and C4-2B cell lysates 24 h after transient transfection with Flag-CK2α expression construct. Control lanes represent empty vector transfected cells. β-Tubulin signal was used as the loading control. Arrows indicate correct band. Full article ">Figure 2
Co-expression of CSNK2A1 and AR genes in prostate cancer patient primary tumor samples. Analysis of co-expression of CSNK2A1 and AR mRNA levels in PCa patient samples from The Cancer Genome Atlas (Pan-Cancer Atlas; n = 494 samples). Correlation analysis and p-values provided within panel. Analysis performed using cBioPortal with Z-score cut-off set at 1.5. RSEM, RNA-Seq by Expectation–Maximization. Full article ">Figure 3
Blocking CK2 expression and activity reduces AR protein levels in PCa cells. (A) LNCaP (left panels) and C4-2 (right panels) cells were transfected with CK2αα’-targeted and control siRNAs. Cells were collected 48 and 72 h post-transfection for analysis by immunoblot. (B) LNCaP, C4-2, and 22Rv1 cells were treated with 80 µM TBB, 10 µM CX-4945, or equivalent concentration of DMSO. Cells were collects at various time points, as labeled above the lanes, for analysis by immunoblot. UnT = untreated cells. Vertical lines indicate non-contiguous lanes. (C) C4-2B and 22Rv1 cells were treated with 20 µM TBB, 40 µM TBB, or equivalent concentration of DMSO. Cells were collected at 24 h for analysis by immunoblot. Mean and 95% confidence intervals for AR protein levels after TBB treatment relative to DMSO treatment are indicated below the AR bands. For all panels: Proteins detected are indicated on the right side of blots, time points analyzed are indicated below the blots, and either actin or β-tubulin were used as loading controls. Arrows indicate correct band. Full article ">Figure 4
Blocking CK2 expression and activity reduces NFκB p65 protein levels and activation in PCa cells. (A) LNCaP cells were transfected with CK2αα’-targeted and control siRNAs. Cells were collected 48 and 72 h post-transfection, as labeled below the blots, for analysis by immunoblot. (B) C4-2B and 22Rv1 cells were treated with 20 µM TBB, 40 µM TBB or equivalent concentration of DMSO as indicated. Cells were collected at 24 h for analysis by immunoblot. Vertical lines indicate non-contiguous lanes. For all panels: proteins detected are indicated on the right side of blots and either actin or β-tubulin were used as loading controls. Arrows indicate correct band. Means and 95% confidence intervals for values relative to siControl or DMSO are indicated below each blot. Full article ">Figure 5
Anti-CK2 nanocapsule RNAi-based systemic treatment reduces expression of CK2, AR and NFκB p65 in 22Rv1 orthotopic xenograft tumors. (A) Orthotopic 22Rv1 tumors were initiated in NOD SCID gamma castrated male mice. When tumors were palpable, mice were treated on days 1, 4 and 7 with TBG-RNAi-CK2 or TBG-RNAi-F7 (control) nanocapsule by tail vein injection (0.02 mg/kg). Tumors were harvested on day 8, 24 h after the last treatment. Tumors were weighed, dissected to remove dead tissue, and reweighed. Mean tumor weights per group are indicated on the left panel and the mean percent of dead tumor tissue removed is indicated on the right panel. TBG-RNAi-CK2, n = 4; TBG-RNAi-F7, n = 3. Error bars indicate standard error. (B) Orthotopic xenograft 22Rv1 tumors from mice treated with TBG-RNAi-CK2 or TBG-RNAi-F7 (control) nanocapsule drugs were subjected to immunoblot analysis. Treatments are indicated above the lanes, and proteins detected are indicated to the right of the panels. Mean expression levels and 95% confidence intervals are indicated below the individual blots. Actin was used as a loading control. Full article ">Figure 6
Androgen is not required for CK2 block-mediated loss of AR protein levels, and AR loss is equivalent in non-malignant RWPE-1 cells. (A) C4-2 and 22Rv1 cells grown under androgen-free conditions were treated with 80 µM TBB or equivalent concentration of DMSO. Cells were collected 48 h post-treatment for analysis by immunoblot. (B) RWPE-1 cells were treated with 80 µM TBB or equivalent concentration of DMSO or transfected with CK2αα’-targeted and control siRNAs. Cells were analyzed by immunoblot at the time points indicated below the panels. For all panels: treatment conditions are indicated above the lanes, and proteins detected indicated to the right of the panels, and actin was used as a loading control. Full article ">Figure 7
CK2 expression and activity influence AR protein half-life and ER stress signaling. (A) 22Rv1 and C4-2B cells were treated with 80 µM TBB or equivalent concentration of DMSO. C4-2B cells were also transfected with CK2αα′-targeted and control siRNAs. Twenty-four hours after TBB or DMSO treatment or 22 h post-transfection, cycloheximide was added to the culture plates, and cells were collected over time as indicated above the blot lanes. Cell lysates were analyzed by immunoblot for AR protein expression, and AR half-life was calculated by linear regression of the quantitated signals. (B) C4-2 and 22Rv1 sample lysates from the experiments presented in <a href="#pharmaceuticals-12-00089-f003" class="html-fig">Figure 3</a>B were analyzed for markers of ER stress and autophagy by immunoblot. (C) AR and CHOP signals were analyzed by immunoblot in C4-2 and 22Rv1 48 h lysates following treatment with TBB or CX-4945. Full article ">Figure 8
CK2 inhibition decreases cell viability and induces loss of mitochondrial membrane potential in enzalutamide-resistant C4-2B prostate cancer cells. (A) C4-2B parental and enzalutamide-resistant cells were treated with 2-fold dilution series of TBB, CX-4945 or equivalent concentrations of DMSO for 72 h. Cell viability was measured by MTS-based Aqueous One assay. Experiment was performed three times. Error bars indicate standard error. * p < 0.05; ** p < 0.01; *** p < 0.001; # p < 0.0001. (B) C4-2B parental and enzalutamide-resistant cells were treated with 50 µM TBB, or equivalent volume DMSO for 2 h. JC-1 was added to the cells 1 h after TBB or DMSO addition. CCCP treatment at 50 µM for the last 30 min of incubation was used as positive control. Experiment was performed three times. Error bars indicate standard error. *** p < 0.001; # p < 0.0001. Full article ">Figure 9
Cartoon summary of the influence of CK2 expression and activity on AR and NFκB p65 protein expression and prostate tumor cell survival as described in this work. Full article ">

20 pages, 3420 KiB

Open AccessArticle

CDK11 Loss Induces Cell Cycle Dysfunction and Death of BRAF and NRAS Melanoma Cells

by Rehana L. Ahmed, Daniel P. Shaughnessy, Todd P. Knutson, Rachel I. Vogel, Khalil Ahmed, Betsy T. Kren and Janeen H. Trembley

Pharmaceuticals 2019, 12(2), 50; https://doi.org/10.3390/ph12020050 - 2 Apr 2019

Cited by 9 | Viewed by 4938

Abstract

Cyclin dependent kinase 11 (CDK11) is a protein kinase that regulates RNA transcription, pre-mRNA splicing, mitosis, and cell death. Targeting of CDK11 expression levels is effective in the experimental treatment of breast and other cancers, but these data are lacking in melanoma. To [...] Read more.

Cyclin dependent kinase 11 (CDK11) is a protein kinase that regulates RNA transcription, pre-mRNA splicing, mitosis, and cell death. Targeting of CDK11 expression levels is effective in the experimental treatment of breast and other cancers, but these data are lacking in melanoma. To understand CDK11 function in melanoma, we evaluated protein and RNA levels of CDK11, Cyclin L1 and Cyclin L2 in benign melanocytes and BRAF- as well as NRAS-mutant melanoma cell lines. We investigated the effectiveness of reducing expression of this survival kinase using RNA interference on viability, clonal survival, and tumorsphere formation in melanoma cell lines. We examined the impact of CDK11 loss in BRAF-mutant melanoma on more than 700 genes important in cancer signaling pathways. Follow-up analysis evaluated how CDK11 loss alters cell cycle function in BRAF- and NRAS-mutant melanoma cells. We present data on CDK11, CCNL1 and CCNL2 mRNA expression in melanoma patients, including prognosis for survival. In sum, we found that CDK11 is necessary for melanoma cell survival, and a major impact of CDK11 loss in melanoma is to cause disruption of the cell cycle distribution with accumulation of G1- and loss of G2/M-phase cancer cells. Full article

(This article belongs to the Special Issue Protein Kinases and Cancer)

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Review

Jump to: Research

8 pages, 567 KiB

Open AccessEditor’s ChoiceReview

Small Molecule Induced FLT3 Degradation

by Sun-Young Han

Pharmaceuticals 2022, 15(3), 320; https://doi.org/10.3390/ph15030320 - 8 Mar 2022

Cited by 3 | Viewed by 3632

Abstract

Target protein degrader is a new paradigm in the small molecule drug discovery field and relates to the term ‘event-driven pharmacology’. Fms-like tyrosine kinase 3 (FLT3) is a significant target for treating acute myeloid leukemia (AML). A few FLT3 kinase inhibitors are currently [...] Read more.

Target protein degrader is a new paradigm in the small molecule drug discovery field and relates to the term ‘event-driven pharmacology’. Fms-like tyrosine kinase 3 (FLT3) is a significant target for treating acute myeloid leukemia (AML). A few FLT3 kinase inhibitors are currently used in the clinic for AML patients. However, resistance to current FLT3 inhibitors has emerged, and strategies to overcome this resistance are required. Small molecules downregulating FLT3 protein level are reported, exhibiting antileukemic effects against AML cell lines. Small molecules with various mechanisms such as Hsp90 inhibition, proteasome inhibition, RET inhibition, and USP10 inhibition are explained. In addition, reports of FLT3 as a client of Hsp90, current knowledge of the ubiquitin proteasome system for FLT3 degradation, the relationship with FLT3 phosphorylation status and susceptibility of FLT3 degradation are discussed. Full article

(This article belongs to the Special Issue Protein Kinases and Cancer)

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26 pages, 1128 KiB

Open AccessReview

CDK4/6 and MAPK—Crosstalk as Opportunity for Cancer Treatment

by Lisa Scheiblecker, Karoline Kollmann and Veronika Sexl

Pharmaceuticals 2020, 13(12), 418; https://doi.org/10.3390/ph13120418 - 24 Nov 2020

Cited by 30 | Viewed by 6768

Abstract

Despite the development of targeted therapies and novel inhibitors, cancer remains an undefeated disease. Resistance mechanisms arise quickly and alternative treatment options are urgently required, which may be partially met by drug combinations. Protein kinases as signaling switchboards are frequently deregulated in cancer [...] Read more.

Despite the development of targeted therapies and novel inhibitors, cancer remains an undefeated disease. Resistance mechanisms arise quickly and alternative treatment options are urgently required, which may be partially met by drug combinations. Protein kinases as signaling switchboards are frequently deregulated in cancer and signify vulnerable nodes and potential therapeutic targets. We here focus on the cell cycle kinase CDK6 and on the MAPK pathway and on their interplay. We also provide an overview on clinical studies examining the effects of combinational treatments currently explored for several cancer types. Full article

(This article belongs to the Special Issue Protein Kinases and Cancer)

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Overview of the best-studied MAPK signaling cascades and their interplay with the cell cycle machinery. MAPK cascades consist of three core kinases. The general pattern of the core kinases is shown in the box on the left. The three core kinases are activated by upstream kinases (MAP4Ks, Ras). Activation is indicated by the arrows. Activated MAPKs translocate into the nucleus (indicated by the dashed arrows) and induce expression of their target genes. Target genes of MAPKs are among others genes encoding D-type cyclins. They bind and activate cell cycle kinases CDK4 and 6 leading to phosphorylation on Rb (indicated by the star symbol) and to release of Rb-mediated repression of E2F target genes resulting in progression of the cell cycle to the S-phase. Members of the CIP/KIP and the INK protein families inhibit CDK4/6 as indicated by the “T-lines”. Full article ">Figure 2
The interplay of CDK4/6 and the MAPK pathways in the context of AP-1. Adapted from [<a href="#B19-pharmaceuticals-13-00418" class="html-bibr">19</a>,<a href="#B41-pharmaceuticals-13-00418" class="html-bibr">41</a>]. Activating signals pass through the MAPK cascade until they reach MAPKs (indicated by the dashed arrows at the top). MAPKs activate ternary complex factors (TCF), MEF2C, ATF2 and JUN (indicated by the arrows) that translocate into the nucleus (indicated by the lower dashed arrows) and induce expression of FOS and JUN. Full article ">Figure 3
Overview of CDK4/6 and MAPK inhibitors. (a) FDA approved small-molecule inhibitors palbociclib, abemaciclib and ribociclib bind to CDK4/6 and prevent phosphorylation of Rb (indicated by the star symbol), which can result in cell cycle arrest in the G1 phase, block of differentiation and survival. (b) Inhibitors of the ERK pathway blocking the prosurvival and proliferative effects of ERK signaling. (c) Inhibitors of p38 are controversial and can have opposing effects as p38 is a tumor suppressor but can also have tumor promoting effects at later stages of cancer development. “T-lines” indicate inhibition, arrows indicate activation and dashed arrows indicate translocation into the nucleus. The arrows at the bottom of each panel show major outcomes of the signaling networks. Full article ">Figure 4
Regulation of transcription mediated by CDK6 and AP-1. CDK6 is not only a cell cycle kinase but also has transcriptional functions. Together with cofactors like JUN (indicated by the star symbol) and potentially also other AP-1 factors it regulates transcription of target genes like VEGF-A [<a href="#B18-pharmaceuticals-13-00418" class="html-bibr">18</a>]. Inhibition of MAPK (indicated by the “T-lines”) blocks activation of AP-1 (indicated by the arrows) and its translocation to the nucleus (indicated by the dashed arrow) and thus might interfere with tumor promoting transcriptional complexes containing CDK6. Blocking of CDK6 with small-molecule inhibitors only inhibits kinase-dependent functions. The transcriptional roles of CDK6 can be dependent or independent of its kinase activity. Thus, treatment with CDK4/6 inhibitors only partially blocks the transcriptional functions of CDK6 (indicated by the dashed “T-line”). Full article ">

11 pages, 2207 KiB

Open AccessReview

Mitogen-Activated Protein Kinase Inhibitors and T-Cell-Dependent Immunotherapy in Cancer

by Sandeep Kumar, Daniel R. Principe, Sunil Kumar Singh, Navin Viswakarma, Gautam Sondarva, Basabi Rana and Ajay Rana

Pharmaceuticals 2020, 13(1), 9; https://doi.org/10.3390/ph13010009 - 7 Jan 2020

Cited by 27 | Viewed by 6258

Abstract

Mitogen-activated protein kinase (MAPK) signaling networks serve to regulate a wide range of physiologic and cancer-associated cell processes. For instance, a variety of oncogenic mutations often lead to hyperactivation of MAPK signaling, thereby enhancing tumor cell proliferation and disease progression. As such, several [...] Read more.

Mitogen-activated protein kinase (MAPK) signaling networks serve to regulate a wide range of physiologic and cancer-associated cell processes. For instance, a variety of oncogenic mutations often lead to hyperactivation of MAPK signaling, thereby enhancing tumor cell proliferation and disease progression. As such, several components of the MAPK signaling network have been proposed as viable targets for cancer therapy. However, the contributions of MAPK signaling extend well beyond the tumor cells, and several MAPK effectors have been identified as key mediators of the tumor microenvironment (TME), particularly with respect to the local immune infiltrate. In fact, a blockade of various MAPK signals has been suggested to fundamentally alter the interaction between tumor cells and T lymphocytes and have been suggested a potential adjuvant to immune checkpoint inhibition in the clinic. Therefore, in this review article, we discuss the various mechanisms through which MAPK family members contribute to T-cell biology, as well as circumstances in which MAPK inhibition may potentiate or limit cancer immunotherapy. Full article

(This article belongs to the Special Issue Protein Kinases and Cancer)

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12 pages, 1351 KiB

Open AccessReview

CDK8-Novel Therapeutic Opportunities

by Ingeborg Menzl, Agnieszka Witalisz-Siepracka and Veronika Sexl

Pharmaceuticals 2019, 12(2), 92; https://doi.org/10.3390/ph12020092 - 19 Jun 2019

Cited by 33 | Viewed by 7263

Abstract

Improvements in cancer therapy frequently stem from the development of new small-molecule inhibitors, paralleled by the identification of biomarkers that can predict the treatment response. Recent evidence supports the idea that cyclin-dependent kinase 8 (CDK8) may represent a potential drug target for breast [...] Read more.

Improvements in cancer therapy frequently stem from the development of new small-molecule inhibitors, paralleled by the identification of biomarkers that can predict the treatment response. Recent evidence supports the idea that cyclin-dependent kinase 8 (CDK8) may represent a potential drug target for breast and prostate cancer, although no CDK8 inhibitors have entered the clinics. As the available inhibitors have been recently reviewed, we focus on the biological functions of CDK8 and provide an overview of the complexity of CDK8-dependent signaling throughout evolution and CDK8-dependent effects that may open novel treatment avenues. Full article

(This article belongs to the Special Issue Protein Kinases and Cancer)

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29 pages, 1261 KiB

Open AccessReview

The Multi-Functional Calcium/Calmodulin Stimulated Protein Kinase (CaMK) Family: Emerging Targets for Anti-Cancer Therapeutic Intervention

by Joshua S. Brzozowski and Kathryn A. Skelding

Pharmaceuticals 2019, 12(1), 8; https://doi.org/10.3390/ph12010008 - 7 Jan 2019

Cited by 50 | Viewed by 7609

Abstract

The importance of Ca²⁺ signalling in key events of cancer cell function and tumour progression, such as proliferation, migration, invasion and survival, has recently begun to be appreciated. Many cellular Ca²⁺-stimulated signalling cascades utilise the intermediate, calmodulin (CaM). The Ca [...] Read more.

The importance of Ca²⁺ signalling in key events of cancer cell function and tumour progression, such as proliferation, migration, invasion and survival, has recently begun to be appreciated. Many cellular Ca²⁺-stimulated signalling cascades utilise the intermediate, calmodulin (CaM). The Ca²⁺/CaM complex binds and activates a variety of enzymes, including members of the multifunctional Ca²⁺/calmodulin-stimulated protein kinase (CaMK) family. These enzymes control a broad range of cancer-related functions in a multitude of tumour types. Herein, we explore the cancer-related functions of these kinases and discuss their potential as targets for therapeutic intervention. Full article

(This article belongs to the Special Issue Protein Kinases and Cancer)

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Schematic representing the domain structure of CaMKK. There are two CaMKK isoforms—CaMKKα and CaMKKβ. CaMKK consists of a unique N-terminal domain (grey), a catalytic domain (red) which contains an ATP binding region, and a regulatory domain (blue) containing overlapping autoinhibitory and calmodulin (CaM) binding regions. Phosphorylation sites are indicated by green balls, with protein kinase A (PKA) phosphorylation sites indicated with red arrows. Full article ">Figure 2
Schematic representing the domain structure of the CaMKI family. There are four CaMKI isoforms—CaMKIα, CaMKIβ, CaMKIγ, and CaMKIδ, with each isoform sharing a similar structure. CaMKI consists of a unique N-terminal domain (grey), adjacent to a catalytic domain (red) which contains an ATP binding region, and a regulatory domain (blue) containing overlapping autoinhibitory and calmodulin (CaM) binding regions. Phosphorylation sites are indicated by green balls. Full article ">Figure 3
Schematic representing the domain structure of the CaMKII family. There are four CaMKII isoforms—CaMKIIα, CaMKIIβ, CaMKIIγ, and CaMKIIδ, with each isoform sharing a similar structure. CaMKII consists of a unique N-terminal domain (grey), adjacent to a catalytic domain (red) which contains an ATP binding region, and a regulatory domain (blue) containing overlapping autoinhibitory and calmodulin (CaM) binding regions. Phosphorylation sites are indicated by green balls. All isoforms also contain a C-terminal association domain (brown), which is involved in the formation of CaMKII multimers. Full article ">Figure 4
Schematic representing the domain structure of the CaMKIV family. The two CaMKIV isoforms—CaMKIVα and CaMKIIβ differ only at their N-terminus. CaMKIV consists of a unique N-terminal domain (grey), adjacent to a catalytic domain (red) which contains an ATP binding region, and a regulatory domain (blue) containing overlapping autoinhibitory and calmodulin (CaM) binding regions. Phosphorylation sites are indicated (green balls). Full article ">Figure 5
Structures of STO-609, KN-62, KN-93, berbamine dihydrochloride and bbd24. Full article ">

21 pages, 7040 KiB

Open AccessReview

Natural Compounds and Derivatives as Ser/Thr Protein Kinase Modulators and Inhibitors

by Barbara Guerra and Olaf-Georg Issinger

Pharmaceuticals 2019, 12(1), 4; https://doi.org/10.3390/ph12010004 - 1 Jan 2019

Cited by 24 | Viewed by 7102

Abstract

The need for new drugs is compelling, irrespective of the disease. Focusing on medical problems in the Western countries, heart disease and cancer are at the moment predominant illnesses. Owing to the fact that ~90% of all 21,000 cellular proteins in humans are [...] Read more.

The need for new drugs is compelling, irrespective of the disease. Focusing on medical problems in the Western countries, heart disease and cancer are at the moment predominant illnesses. Owing to the fact that ~90% of all 21,000 cellular proteins in humans are regulated by phosphorylation/dephosphorylation it is not surprising that the enzymes catalysing these reactions (i.e., protein kinases and phosphatases, respectively) have attracted considerable attention in the recent past. Protein kinases are major team players in cell signalling. In tumours, these enzymes are found to be mutated disturbing the proper function of signalling pathways and leading to uncontrolled cellular growth and sustained malignant behaviour. Hence, the search for small-molecule inhibitors targeting the altered protein kinase molecules in tumour cells has become a major research focus in the academia and pharmaceutical companies. Full article

(This article belongs to the Special Issue Protein Kinases and Cancer)

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