Interleukin-1 receptor-associated kinase 1 (IRAK1), an essential mediator of innate immunity and inflammatory responses, is constitutively active in multiple cancers. We evaluated the role of IRAK1 in acute myeloid leukemia (AML) and... more
Interleukin-1 receptor-associated kinase 1 (IRAK1), an essential mediator of innate immunity and inflammatory responses, is constitutively active in multiple cancers. We evaluated the role of IRAK1 in acute myeloid leukemia (AML) and assessed the inhibitory activity of multikinase inhibitor pacritinib on IRAK1 in AML. We demonstrated that IRAK1 is overexpressed in AML and provides a survival signal to AML cells. Genetic knockdown of IRAK1 in primary AML samples and xenograft model showed a significant reduction in leukemia burden. Kinase profiling indicated pacritinib has potent inhibitory activity against IRAK1. Computational modeling combined with site-directed mutagenesis demonstrated high-affinity binding of pacritinib to the IRAK1 kinase domain. Pacritinib exposure reduced IRAK1 phosphorylation in AML cells. A higher percentage of primary AML samples showed robust sensitivity to pacritinib, which inhibits FLT3, JAK2, and IRAK1, relative to FLT3 inhibitor quizartinib or JAK1/2 i...
Research Interests:
To study the problem of acquired resistance to widely used anti-cancer drugs that target the 170 kDa topoisomerase IIα (topo IIα), a drug-resistant human small-cell lung cancer cell line, H209/VP, was selected in VP-16. H209/VP cells... more
To study the problem of acquired resistance to widely used anti-cancer drugs that target the 170 kDa topoisomerase IIα (topo IIα), a drug-resistant human small-cell lung cancer cell line, H209/VP, was selected in VP-16. H209/VP cells express reduced levels of the 170 kDa ...
Research Interests:
Research Interests:
Recent studies have shown that 3-Deazaneplanocin A (DZNep), a histone methyltransferase inhibitor, disrupts polycomb-repressive complex 2 (PRC2), and preferentially induces apoptosis in cancer cells, including acute myeloid leukemia... more
Recent studies have shown that 3-Deazaneplanocin A (DZNep), a histone methyltransferase inhibitor, disrupts polycomb-repressive complex 2 (PRC2), and preferentially induces apoptosis in cancer cells, including acute myeloid leukemia (AML). However, the underlying molecular mechanisms are not well understood. The present study demonstrates that DZNep induces robust apoptosis in AML cell lines, primary cells, and targets CD34+CD38− leukemia stem cell (LSC)–enriched subpopulations. Using RNA interference (RNAi), gene expression profiling, and ChIP, we identified that TXNIP, a major redox control molecule, plays a crucial role in DZNep-induced apoptosis. We show that disruption of PRC2, either by DZNep treatment or EZH2 knockdown, reactivates TXNIP, inhibits thioredoxin activity, and increases reactive oxygen species (ROS), leading to apoptosis. Furthermore, we show that TXNIP is down-regulated in AML and is a direct target of PRC2-mediated gene silencing. Consistent with the ROS accumu...
Research Interests: Biology, Enzyme Inhibitors, Apoptosis, Medicine, Gene Silencing, and 15 moreEpigenomics, Adenosine, Humans, Mice, Female, Animals, Blood, Clinical Sciences, Chromatin Immunoprecipitation, Cell Proliferation, DNA binding proteins, Polycomb group proteins, Gene expression profiling, Cardiovascular medicine and haematology, and Paediatrics and reproductive medicine
Research Interests:
Research Interests: Engineering, Physics, Chemistry, Biology, Apoptosis, and 15 moreMedicine, Gene expression, Multidisciplinary, Caspases, Cell line, Acute Myeloid Leukemia, Adenosine, Humans, Multiple Myeloma, PLoS one, Cell Proliferation, Gene Expression Analysis, Antitumor Activity, DNA binding proteins, and Drug synergism
Research Interests:
Research Interests: Cell line, Adenosine, Humans, Methylation, DNA methylation, and 15 moreCpG islands, Cluster Analysis, Histones, Chromatin Immunoprecipitation, Molecular Cancer Therapeutics, Hydroxamic Acids, DNA binding proteins, Breast Cancer Cells, Gene expression profiling, Histone deacetylase inhibitors, Immunoblotting, Breast Neoplasms, Azacitidine, reverse transcriptase polymerase chain reaction, and Pharmacology and pharmaceutical sciences
Colorectal cancer patients often relapse after chemotherapy, owing to the survival of stem or progenitor cells referred to as cancer stem cells (CSCs). Although tumor stromal factors are known to contribute to chemoresistance, it remains... more
Colorectal cancer patients often relapse after chemotherapy, owing to the survival of stem or progenitor cells referred to as cancer stem cells (CSCs). Although tumor stromal factors are known to contribute to chemoresistance, it remains not fully understood how CSCs in the hypoxic tumor microenvironment escape the chemotherapy. Here, we report that hypoxia-inducible factor (HIF-1α) and cancer-associated fibroblasts (CAFs)-secreted TGF-β2 converge to activate the expression of hedgehog transcription factor GLI2 in CSCs, resulting in increased stemness/dedifferentiation and intrinsic resistance to chemotherapy. Genetic or small-molecule inhibitor-based ablation of HIF-1α/TGF-β2-mediated GLI2 signaling effectively reversed the chemoresistance caused by the tumor microenvironment. Importantly, high expression levels of HIF-1α/TGF-β2/GLI2 correlated robustly with the patient relapse following chemotherapy, highlighting a potential biomarker and therapeutic target for chemoresistance in ...