Androgen receptor (AR) plays a central role in prostate tumor biology. Here, we studied the impac... more Androgen receptor (AR) plays a central role in prostate tumor biology. Here, we studied the impact of yes‐associated protein (YAP) oncogene, a nuclear effector of the hippo tumor suppressor network, on AR signaling. We first showed that native YAP formed protein complexes with endogenous AR, and the complex formation that mainly occurred in cell nuclei was enhanced by androgen, as revealed by immunoprecipitation (IP) and western blots. Our promoter reporter analysis demonstrated that enforced YAP expression increased the activation of AR‐dependent promoter reporter gene, and that the carboxyl‐terminal site of YAP, which consists of WW and coiled‐coiled domains, appeared to be responsible for AR transactivation. Chromatin‐IP experiment demonstrated that YAP interacted with the DNA regions where AR also binds, and that androgen enhanced the YAP and chromatin DNA complexes. We also provide evidence that YAP induction promoted an androgen‐dependent and ‐independent cell growth, and that YAP knockdown had the opposite effects. Our data indicate that YAP is a binding partner and physiologic positive regulator of AR and suggest that altered Hippo‐YAP signaling could play a critical role in prostate tumor progression in humans.
Metastatic castration-resistant prostate cancer is morbid and lethal. The transcriptional coregul... more Metastatic castration-resistant prostate cancer is morbid and lethal. The transcriptional coregulator YAP1 (Yes-associated protein 1) is a nuclear effector of the Hippo pathway. The Hippo pathway regulates cell growth, motility, and carcinogenesis. Here, we investigated biochemical and functional interactions between YAP1 and the nuclear factor (NF) kappa B/RELA subunit in prostate cancer cell models. We demonstrated that endogenous YAP1 and RELA form protein complexes in the cell, as revealed by co-immunoprecipitation and western blotting. Compared with control, we found that combined treatment of cells with androgen and SDF1a (stromal cell-derived factor-1 alpha) or RANKL (receptor activator of NF-kappa Β ligand) enhanced the protein-protein interaction between YAP1 and RELA, as showed by proximity ligation assay. Our confocal microscopy experiment further showed that combined SDF1a and androgen treatment augmented the YAP1 and RELA colocalization relative to single-agent. Moreover, our promoter-reporter and RNAi experiments showed that genetic silencing YAP1 or TEAD protein, a key mediator of the YAP1 transcription, significantly reduced the NF-Kappa B promoter-reporter gene activity. Also, disruption of YAP1 activity by genetic and small molecule attenuated endogenous protein-protein interaction between TEAD and RELA. Furthermore, controlled expression of MST1/STK4, a potent inhibitor of YAP1, suppressed the NF-Kappa B-promoter reporter activity. Additionally, our unbiased bioinformatics analysis of the exiting ChIP-seq (chromatin immunoprecipitation-sequencing) data identified several genes likely co-regulated by the TEAD1-4 and NF-Kappa B transcription factors. Besides, our computational analysis of the TCGA and Stand Up To Cancer (SU2C) prostate cancer data sets indicated that expression of YAP/TEAD and NF-kappa B/RELA correlates in clinical cases. These findings suggest that cooperative androgen and cytokine signaling regulates Hippo/YAP and NF-Kappa B interaction and their functions. These may have critical roles in advanced prostate cancer downstream of the Hippo pathway. Citation Format: Bekir Cinar, Marwah M. Al-Mathkour, Abdulrahman M. Dwead, Ava M. Boston, Michael S. Lewis, Carlos S. Moreno. The YAP1/TEAD and NF-Kappa B transcription factors may cooperate to mediate prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1448.
Androgen receptor (AR) plays a central role in prostate tumor biology. Here, we studied the impac... more Androgen receptor (AR) plays a central role in prostate tumor biology. Here, we studied the impact of yes‐associated protein (YAP) oncogene, a nuclear effector of the hippo tumor suppressor network, on AR signaling. We first showed that native YAP formed protein complexes with endogenous AR, and the complex formation that mainly occurred in cell nuclei was enhanced by androgen, as revealed by immunoprecipitation (IP) and western blots. Our promoter reporter analysis demonstrated that enforced YAP expression increased the activation of AR‐dependent promoter reporter gene, and that the carboxyl‐terminal site of YAP, which consists of WW and coiled‐coiled domains, appeared to be responsible for AR transactivation. Chromatin‐IP experiment demonstrated that YAP interacted with the DNA regions where AR also binds, and that androgen enhanced the YAP and chromatin DNA complexes. We also provide evidence that YAP induction promoted an androgen‐dependent and ‐independent cell growth, and that...
Supplementary Figure 2 from Heterogeneous Nuclear Ribonucleoprotein K Is a Novel Regulator of And... more Supplementary Figure 2 from Heterogeneous Nuclear Ribonucleoprotein K Is a Novel Regulator of Androgen Receptor Translation
Supplementary Figure 3 from Heterogeneous Nuclear Ribonucleoprotein K Is a Novel Regulator of And... more Supplementary Figure 3 from Heterogeneous Nuclear Ribonucleoprotein K Is a Novel Regulator of Androgen Receptor Translation
Supplementary Legends for Figures 1-5 from Heterogeneous Nuclear Ribonucleoprotein K Is a Novel R... more Supplementary Legends for Figures 1-5 from Heterogeneous Nuclear Ribonucleoprotein K Is a Novel Regulator of Androgen Receptor Translation
Supplementary Figure 1 from Heterogeneous Nuclear Ribonucleoprotein K Is a Novel Regulator of And... more Supplementary Figure 1 from Heterogeneous Nuclear Ribonucleoprotein K Is a Novel Regulator of Androgen Receptor Translation
Heparin-binding epidermal growth factor-like growth factor (HB-EGF), an ErbB1 ligand and prostate... more Heparin-binding epidermal growth factor-like growth factor (HB-EGF), an ErbB1 ligand and prostate stromal growth factor, is an antagonist of androgen receptor (AR) function. In the LNCaP prostate cancer model, HB-EGF reduced AR protein levels and AR transactivation without affecting AR mRNA level or protein turnover. The signal to attenuate AR was mediated by the mammalian target of rapamycin, as shown by genetic and pharmacologic methods, and was independent of ErbB2/HER-2, extracellular signal-regulated kinase 1/2, and p38 mitogen-activated protein kinase pathways. Additional evidence suggests that AR protein levels are highly sensitive to regulation by cap-dependent mRNA translation. These findings reveal a novel mechanism for regulation of AR by a classic growth factor system and indicate that a rapamycin-sensitive post-transcriptional pathway can attenuate or possibly bypass AR-mediated signaling.
The serine-threonine kinase, Akt, has been linked to cholesterol-sensitive signaling mechanisms, ... more The serine-threonine kinase, Akt, has been linked to cholesterol-sensitive signaling mechanisms, suggesting a possible means whereby cholesterol might affect tumor cell growth and survival. However, it has not been shown whether Akt itself, as distinct from upstream components of the pathway (e.g., membrane phosphoinositides), can be directly responsible for cholesterol-mediated effects. Consistent with this possibility, we identified an Akt1 subpopulation in cholesterol-rich lipid raft fractions prepared from LNCaP human prostate cancer cells. Phosphorylation of this Akt subspecies was ablated with methyl-β-cyclodextrin, a cholesterol-binding compound, under conditions where nonlipid raft-resident Akt was unaffected. A myristoylated Akt1 (MyrAkt1) fusion protein expressed in LNCaP cells was found to be highly enriched in lipid rafts, indicating that oncogenic Akt is overrepresented in cholesterol-rich membranes compared with wild-type Akt. Notably, lipid raft-resident MyrAkt1 exhib...
Figure S1 from Post-Transcriptional Regulation of the Androgen Receptor by Mammalian Target of Ra... more Figure S1 from Post-Transcriptional Regulation of the Androgen Receptor by Mammalian Target of Rapamycin
The transcriptional coactivator YAP1 is a key nuclear effector of the Hippo pathway. STK4/MST1 an... more The transcriptional coactivator YAP1 is a key nuclear effector of the Hippo pathway. STK4/MST1 and LATS1/2 are the core kinase components of the Hippo pathway, which restricts organ size and prevents tumorigenesis by attenuating cell proliferation and inducing cell death. Previously, we have reported that STK4/Hippo-YAP1 signaling could play a critical role in prostate cancer progression and therapeutic relapse. Here, we investigated the effects of androgen hormone signaling on YAP1 expression and post-transcriptional modifications in prostate cancer cells. We demonstrated that androgen exposure reduced Ser127 phosphorylation on YAP1 in a time-dependent manner in the castration-sensitive prostate cancer cell line, LNCaP, but without altering the levels of YAP1-Ser127 phosphorylation in the C4-2 cell line, a castration-resistant subline of LNCaP cells. As demonstrated by imaging and cell fractionation methods, androgen exposure promoted the nuclear accumulation of YAP1 in LNCaP; howe...
Background: Currently, there is no effective pharmacotherapy for metastatic castration-resistant ... more Background: Currently, there is no effective pharmacotherapy for metastatic castration-resistant prostate cancer (mCRPC). The mechanisms underlying mCRPC are not clearly understood, thus hindering rational-based drug design. Evidence suggests that signal transducer and activator of transcription 3 (STAT3) and 5a/b (STAT5a/b), key components of the JAK/STAT pathway, play a significant role in aggressive PC. However, expression of STAT3/5 in prostate tumor samples have not been studied. Here, we evaluated the possible role of STAT3/5a in aggressive PC. Materials and Methods: Expression of STAT3 and STAT5a in high grade PC (HGPC, n=15) and in benign prostatic hyperplasia (BPH, n=15) tissue sections were evaluated by immunohistochemistry (IHC) according to the protocol approved by Institutional Review Board. Age ranged from 59 to 95 years (median = 81) in the former and 57 years to 86 years (median = 68 years) in the latter category. In addition, the effects of STAT inhibitor, Pimozide,...
Background: Currently, there is no effective pharmacotherapy for metastatic castration-resistant ... more Background: Currently, there is no effective pharmacotherapy for metastatic castration-resistant prostate cancer (mCRPC). The mechanisms underlying mCRPC are not clearly understood, thus hindering rational-based drug design. Evidence suggests that signal transducer and activator of transcription 3 (STAT3) and 5a/b (STAT5a/b), key components of the JAK/STAT pathway, play a significant role in aggressive PC. However, expression of STAT3/5 in prostate tumor samples have not been studied. Here, we evaluated the possible role of STAT3/5a in aggressive PC. Materials and Methods: Expression of STAT3 and STAT5a in high grade PC (HGPC, n=15) and in benign prostatic hyperplasia (BPH, n=15) tissue sections were evaluated by immunohistochemistry (IHC) according to the protocol approved by Institutional Review Board. Age ranged from 59 to 95 years (median = 81) in the former and 57 years to 86 years (median = 68 years) in the latter category. In addition, the effects of STAT inhibitor, Pimozide, on androgen-sensitive LNCaP and its castration-resistant subline C4-2 PC cell growth were assessed in vitro. Results: A strong nuclear immunoreactivity for STAT3 and STAT5a in 93% (n=14) and 80% (n=12) of HGPC cases, respectively, were observed. Only one BPH case showed strong STAT3 expression. Focal and weak positivity for STAT3 and STAT5a were noted in 47% (n=7) and 67% (n=10) of BPH cases. None of the BPH cases showed strong STAT5a expression. HGPC cases showed significantly higher STAT3 positivity compared with BPH (p=0.01). No significant differences were observed for STAT5a expression between HGPC and BPH group (p=0.4). However, multifocal or diffuse and strong STAT3 (p<0.0001) and STAT5a (p<0.0001) expression was significantly higher in HGRPC than BPH. Pimozide exposure significantly inhibited LNCaP cell proliferation at 10 μM and C4-2 cell proliferation at 20 μM concentration. Conclusion: Our results demonstrate that increased expression of STAT3 and STAT5a may serve as a predictive biomarker for efficacy of the JAK/STAT targeted therapy. Since JAK/STAT and androgen receptor signaling are functionally synergistic in contributing PC progression, the inhibition of JAK/STAT-alone or in combination with AR may lead to a novel treatment modality for mCRPC. Citation Format: Sambit K. Mohanty, Kader Yagiz, Luthringer Luthringer, Mahul B. Amin, Serhan Alkan, Bekir Cinar. STAT3 and STAT5a are potential therapeutic targets in castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5707. doi:10.1158/1538-7445.AM2017-5707
American journal of clinical and experimental urology, 2021
The Hippo pathway controls several biological processes, including cell growth, differentiation, ... more The Hippo pathway controls several biological processes, including cell growth, differentiation, motility, stemness, cell contact, immune cell maturation, organ size, and tumorigenesis. The Hippo pathway core kinases MST1/2 and LATS1/2 in mammals phosphorylate and inactivate YAP1 signaling. Increasing evidence indicates that loss of MST1/2 and LATS1/2 function is linked to the biology of many cancer types with poorer outcomes, likely due to the activation of oncogenic YAP1/TEAD signaling. Therefore, there is a renewed interest in blocking the YAP1/TEAD functions to prevent cancer growth. This review introduces the Hippo pathway components and examines their role and therapeutic potentials in prostate, kidney, and bladder cancer.
The EPHA3 protein tyrosine kinase, a member of the ephrin receptor family, regulates cell fate, c... more The EPHA3 protein tyrosine kinase, a member of the ephrin receptor family, regulates cell fate, cell motility, and cell–cell interaction. These cellular events are critical for tissue development, immunological responses, and the processes of tumorigenesis. Earlier studies revealed that signaling via the STK4-encoded MST1 serine-threonine protein kinase, a core component of the Hippo pathway, attenuated EPHA3 expression. Here, we investigated the mechanism by which MST1 regulates EPHA3. Our findings have revealed that the transcriptional regulators YAP1 and TEAD1 are crucial activators of EPHA3 transcription. Silencing YAP1 and TEAD1 suppressed the EPHA3 protein and mRNA levels. In addition, we identified putative TEAD enhancers in the distal EPHA3 promoter, where YAP1 and TEAD1 bind and promote EPHA3 expression. Furthermore, EPHA3 knockout by CRISPR/Cas9 technology reduced cell–cell interaction and cell motility. These findings demonstrate that EPHA3 is transcriptionally regulated ...
Androgen receptor (AR) plays a central role in prostate tumor biology. Here, we studied the impac... more Androgen receptor (AR) plays a central role in prostate tumor biology. Here, we studied the impact of yes‐associated protein (YAP) oncogene, a nuclear effector of the hippo tumor suppressor network, on AR signaling. We first showed that native YAP formed protein complexes with endogenous AR, and the complex formation that mainly occurred in cell nuclei was enhanced by androgen, as revealed by immunoprecipitation (IP) and western blots. Our promoter reporter analysis demonstrated that enforced YAP expression increased the activation of AR‐dependent promoter reporter gene, and that the carboxyl‐terminal site of YAP, which consists of WW and coiled‐coiled domains, appeared to be responsible for AR transactivation. Chromatin‐IP experiment demonstrated that YAP interacted with the DNA regions where AR also binds, and that androgen enhanced the YAP and chromatin DNA complexes. We also provide evidence that YAP induction promoted an androgen‐dependent and ‐independent cell growth, and that YAP knockdown had the opposite effects. Our data indicate that YAP is a binding partner and physiologic positive regulator of AR and suggest that altered Hippo‐YAP signaling could play a critical role in prostate tumor progression in humans.
Metastatic castration-resistant prostate cancer is morbid and lethal. The transcriptional coregul... more Metastatic castration-resistant prostate cancer is morbid and lethal. The transcriptional coregulator YAP1 (Yes-associated protein 1) is a nuclear effector of the Hippo pathway. The Hippo pathway regulates cell growth, motility, and carcinogenesis. Here, we investigated biochemical and functional interactions between YAP1 and the nuclear factor (NF) kappa B/RELA subunit in prostate cancer cell models. We demonstrated that endogenous YAP1 and RELA form protein complexes in the cell, as revealed by co-immunoprecipitation and western blotting. Compared with control, we found that combined treatment of cells with androgen and SDF1a (stromal cell-derived factor-1 alpha) or RANKL (receptor activator of NF-kappa Β ligand) enhanced the protein-protein interaction between YAP1 and RELA, as showed by proximity ligation assay. Our confocal microscopy experiment further showed that combined SDF1a and androgen treatment augmented the YAP1 and RELA colocalization relative to single-agent. Moreover, our promoter-reporter and RNAi experiments showed that genetic silencing YAP1 or TEAD protein, a key mediator of the YAP1 transcription, significantly reduced the NF-Kappa B promoter-reporter gene activity. Also, disruption of YAP1 activity by genetic and small molecule attenuated endogenous protein-protein interaction between TEAD and RELA. Furthermore, controlled expression of MST1/STK4, a potent inhibitor of YAP1, suppressed the NF-Kappa B-promoter reporter activity. Additionally, our unbiased bioinformatics analysis of the exiting ChIP-seq (chromatin immunoprecipitation-sequencing) data identified several genes likely co-regulated by the TEAD1-4 and NF-Kappa B transcription factors. Besides, our computational analysis of the TCGA and Stand Up To Cancer (SU2C) prostate cancer data sets indicated that expression of YAP/TEAD and NF-kappa B/RELA correlates in clinical cases. These findings suggest that cooperative androgen and cytokine signaling regulates Hippo/YAP and NF-Kappa B interaction and their functions. These may have critical roles in advanced prostate cancer downstream of the Hippo pathway. Citation Format: Bekir Cinar, Marwah M. Al-Mathkour, Abdulrahman M. Dwead, Ava M. Boston, Michael S. Lewis, Carlos S. Moreno. The YAP1/TEAD and NF-Kappa B transcription factors may cooperate to mediate prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1448.
Androgen receptor (AR) plays a central role in prostate tumor biology. Here, we studied the impac... more Androgen receptor (AR) plays a central role in prostate tumor biology. Here, we studied the impact of yes‐associated protein (YAP) oncogene, a nuclear effector of the hippo tumor suppressor network, on AR signaling. We first showed that native YAP formed protein complexes with endogenous AR, and the complex formation that mainly occurred in cell nuclei was enhanced by androgen, as revealed by immunoprecipitation (IP) and western blots. Our promoter reporter analysis demonstrated that enforced YAP expression increased the activation of AR‐dependent promoter reporter gene, and that the carboxyl‐terminal site of YAP, which consists of WW and coiled‐coiled domains, appeared to be responsible for AR transactivation. Chromatin‐IP experiment demonstrated that YAP interacted with the DNA regions where AR also binds, and that androgen enhanced the YAP and chromatin DNA complexes. We also provide evidence that YAP induction promoted an androgen‐dependent and ‐independent cell growth, and that...
Supplementary Figure 2 from Heterogeneous Nuclear Ribonucleoprotein K Is a Novel Regulator of And... more Supplementary Figure 2 from Heterogeneous Nuclear Ribonucleoprotein K Is a Novel Regulator of Androgen Receptor Translation
Supplementary Figure 3 from Heterogeneous Nuclear Ribonucleoprotein K Is a Novel Regulator of And... more Supplementary Figure 3 from Heterogeneous Nuclear Ribonucleoprotein K Is a Novel Regulator of Androgen Receptor Translation
Supplementary Legends for Figures 1-5 from Heterogeneous Nuclear Ribonucleoprotein K Is a Novel R... more Supplementary Legends for Figures 1-5 from Heterogeneous Nuclear Ribonucleoprotein K Is a Novel Regulator of Androgen Receptor Translation
Supplementary Figure 1 from Heterogeneous Nuclear Ribonucleoprotein K Is a Novel Regulator of And... more Supplementary Figure 1 from Heterogeneous Nuclear Ribonucleoprotein K Is a Novel Regulator of Androgen Receptor Translation
Heparin-binding epidermal growth factor-like growth factor (HB-EGF), an ErbB1 ligand and prostate... more Heparin-binding epidermal growth factor-like growth factor (HB-EGF), an ErbB1 ligand and prostate stromal growth factor, is an antagonist of androgen receptor (AR) function. In the LNCaP prostate cancer model, HB-EGF reduced AR protein levels and AR transactivation without affecting AR mRNA level or protein turnover. The signal to attenuate AR was mediated by the mammalian target of rapamycin, as shown by genetic and pharmacologic methods, and was independent of ErbB2/HER-2, extracellular signal-regulated kinase 1/2, and p38 mitogen-activated protein kinase pathways. Additional evidence suggests that AR protein levels are highly sensitive to regulation by cap-dependent mRNA translation. These findings reveal a novel mechanism for regulation of AR by a classic growth factor system and indicate that a rapamycin-sensitive post-transcriptional pathway can attenuate or possibly bypass AR-mediated signaling.
The serine-threonine kinase, Akt, has been linked to cholesterol-sensitive signaling mechanisms, ... more The serine-threonine kinase, Akt, has been linked to cholesterol-sensitive signaling mechanisms, suggesting a possible means whereby cholesterol might affect tumor cell growth and survival. However, it has not been shown whether Akt itself, as distinct from upstream components of the pathway (e.g., membrane phosphoinositides), can be directly responsible for cholesterol-mediated effects. Consistent with this possibility, we identified an Akt1 subpopulation in cholesterol-rich lipid raft fractions prepared from LNCaP human prostate cancer cells. Phosphorylation of this Akt subspecies was ablated with methyl-β-cyclodextrin, a cholesterol-binding compound, under conditions where nonlipid raft-resident Akt was unaffected. A myristoylated Akt1 (MyrAkt1) fusion protein expressed in LNCaP cells was found to be highly enriched in lipid rafts, indicating that oncogenic Akt is overrepresented in cholesterol-rich membranes compared with wild-type Akt. Notably, lipid raft-resident MyrAkt1 exhib...
Figure S1 from Post-Transcriptional Regulation of the Androgen Receptor by Mammalian Target of Ra... more Figure S1 from Post-Transcriptional Regulation of the Androgen Receptor by Mammalian Target of Rapamycin
The transcriptional coactivator YAP1 is a key nuclear effector of the Hippo pathway. STK4/MST1 an... more The transcriptional coactivator YAP1 is a key nuclear effector of the Hippo pathway. STK4/MST1 and LATS1/2 are the core kinase components of the Hippo pathway, which restricts organ size and prevents tumorigenesis by attenuating cell proliferation and inducing cell death. Previously, we have reported that STK4/Hippo-YAP1 signaling could play a critical role in prostate cancer progression and therapeutic relapse. Here, we investigated the effects of androgen hormone signaling on YAP1 expression and post-transcriptional modifications in prostate cancer cells. We demonstrated that androgen exposure reduced Ser127 phosphorylation on YAP1 in a time-dependent manner in the castration-sensitive prostate cancer cell line, LNCaP, but without altering the levels of YAP1-Ser127 phosphorylation in the C4-2 cell line, a castration-resistant subline of LNCaP cells. As demonstrated by imaging and cell fractionation methods, androgen exposure promoted the nuclear accumulation of YAP1 in LNCaP; howe...
Background: Currently, there is no effective pharmacotherapy for metastatic castration-resistant ... more Background: Currently, there is no effective pharmacotherapy for metastatic castration-resistant prostate cancer (mCRPC). The mechanisms underlying mCRPC are not clearly understood, thus hindering rational-based drug design. Evidence suggests that signal transducer and activator of transcription 3 (STAT3) and 5a/b (STAT5a/b), key components of the JAK/STAT pathway, play a significant role in aggressive PC. However, expression of STAT3/5 in prostate tumor samples have not been studied. Here, we evaluated the possible role of STAT3/5a in aggressive PC. Materials and Methods: Expression of STAT3 and STAT5a in high grade PC (HGPC, n=15) and in benign prostatic hyperplasia (BPH, n=15) tissue sections were evaluated by immunohistochemistry (IHC) according to the protocol approved by Institutional Review Board. Age ranged from 59 to 95 years (median = 81) in the former and 57 years to 86 years (median = 68 years) in the latter category. In addition, the effects of STAT inhibitor, Pimozide,...
Background: Currently, there is no effective pharmacotherapy for metastatic castration-resistant ... more Background: Currently, there is no effective pharmacotherapy for metastatic castration-resistant prostate cancer (mCRPC). The mechanisms underlying mCRPC are not clearly understood, thus hindering rational-based drug design. Evidence suggests that signal transducer and activator of transcription 3 (STAT3) and 5a/b (STAT5a/b), key components of the JAK/STAT pathway, play a significant role in aggressive PC. However, expression of STAT3/5 in prostate tumor samples have not been studied. Here, we evaluated the possible role of STAT3/5a in aggressive PC. Materials and Methods: Expression of STAT3 and STAT5a in high grade PC (HGPC, n=15) and in benign prostatic hyperplasia (BPH, n=15) tissue sections were evaluated by immunohistochemistry (IHC) according to the protocol approved by Institutional Review Board. Age ranged from 59 to 95 years (median = 81) in the former and 57 years to 86 years (median = 68 years) in the latter category. In addition, the effects of STAT inhibitor, Pimozide, on androgen-sensitive LNCaP and its castration-resistant subline C4-2 PC cell growth were assessed in vitro. Results: A strong nuclear immunoreactivity for STAT3 and STAT5a in 93% (n=14) and 80% (n=12) of HGPC cases, respectively, were observed. Only one BPH case showed strong STAT3 expression. Focal and weak positivity for STAT3 and STAT5a were noted in 47% (n=7) and 67% (n=10) of BPH cases. None of the BPH cases showed strong STAT5a expression. HGPC cases showed significantly higher STAT3 positivity compared with BPH (p=0.01). No significant differences were observed for STAT5a expression between HGPC and BPH group (p=0.4). However, multifocal or diffuse and strong STAT3 (p<0.0001) and STAT5a (p<0.0001) expression was significantly higher in HGRPC than BPH. Pimozide exposure significantly inhibited LNCaP cell proliferation at 10 μM and C4-2 cell proliferation at 20 μM concentration. Conclusion: Our results demonstrate that increased expression of STAT3 and STAT5a may serve as a predictive biomarker for efficacy of the JAK/STAT targeted therapy. Since JAK/STAT and androgen receptor signaling are functionally synergistic in contributing PC progression, the inhibition of JAK/STAT-alone or in combination with AR may lead to a novel treatment modality for mCRPC. Citation Format: Sambit K. Mohanty, Kader Yagiz, Luthringer Luthringer, Mahul B. Amin, Serhan Alkan, Bekir Cinar. STAT3 and STAT5a are potential therapeutic targets in castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5707. doi:10.1158/1538-7445.AM2017-5707
American journal of clinical and experimental urology, 2021
The Hippo pathway controls several biological processes, including cell growth, differentiation, ... more The Hippo pathway controls several biological processes, including cell growth, differentiation, motility, stemness, cell contact, immune cell maturation, organ size, and tumorigenesis. The Hippo pathway core kinases MST1/2 and LATS1/2 in mammals phosphorylate and inactivate YAP1 signaling. Increasing evidence indicates that loss of MST1/2 and LATS1/2 function is linked to the biology of many cancer types with poorer outcomes, likely due to the activation of oncogenic YAP1/TEAD signaling. Therefore, there is a renewed interest in blocking the YAP1/TEAD functions to prevent cancer growth. This review introduces the Hippo pathway components and examines their role and therapeutic potentials in prostate, kidney, and bladder cancer.
The EPHA3 protein tyrosine kinase, a member of the ephrin receptor family, regulates cell fate, c... more The EPHA3 protein tyrosine kinase, a member of the ephrin receptor family, regulates cell fate, cell motility, and cell–cell interaction. These cellular events are critical for tissue development, immunological responses, and the processes of tumorigenesis. Earlier studies revealed that signaling via the STK4-encoded MST1 serine-threonine protein kinase, a core component of the Hippo pathway, attenuated EPHA3 expression. Here, we investigated the mechanism by which MST1 regulates EPHA3. Our findings have revealed that the transcriptional regulators YAP1 and TEAD1 are crucial activators of EPHA3 transcription. Silencing YAP1 and TEAD1 suppressed the EPHA3 protein and mRNA levels. In addition, we identified putative TEAD enhancers in the distal EPHA3 promoter, where YAP1 and TEAD1 bind and promote EPHA3 expression. Furthermore, EPHA3 knockout by CRISPR/Cas9 technology reduced cell–cell interaction and cell motility. These findings demonstrate that EPHA3 is transcriptionally regulated ...
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