Targeting CDK9: a promising therapeutic opportunity in prostate cancer

Rahaman, Muhammed H.; Kumarasiri, Malika; Mekonnen, Laychiluh; Yu, Mingfeng; Diab, Sarah; Albrecht, Hugo; Milne, Robert W.; Wang, Shudong

doi:10.1530/erc-16-0299

Cited by 60 publications

(65 citation statements)

References 132 publications

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“…CDK9, a member of the cdc2‐like serine/threonine kinase family, plays an important role in promoting cell proliferation and contribute to cancer . CDK9 is a crucial transcriptional regulator, and might serve as a new and better therapeutic opportunity for cancers treatment . Consistent with previous studies, we found that inhibition of CDK9 could suppress HCC cells proliferation, induce cell cycle at G0/G1 arrest, and apoptosis, which could be rescued by overexpression of CDK9.…”

Section: Discussionsupporting

confidence: 90%

miR‐206 inhibits the growth of hepatocellular carcinoma cells via targeting CDK9

et al. 2017

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AbstractmiR‐206 plays an important role in regulating the growth of multiple cancer cells. Cyclin‐dependent kinase 9 (CDK9) stimulates the production of abundant prosurvival proteins, leading to impaired apoptosis of cancer cells. However, it is unknown whether CDK9 is involved in the miR‐206‐mediated growth suppression of hepatocellular carcinoma (HCC) cells. In this study, we found that the expression level of miR‐206 was significantly lower in HCC cell lines than that in normal hepatic cell line (L02). Meanwhile, CDK9 was upregulated in HCC cell lines. Moreover, miR‐206 downregulated CDK9 in HCC cells via directly binding to its mRNA 3′ UTR, which resulted in a decrease of RNA PolII Ser2 phosphorylation and Mcl‐1 level. Additionally, miR‐206 suppressed the cell proliferation, and induced cell cycle arrest and apoptosis. Similarly, silence or inhibition of CDK9 also repressed the cell proliferation, and induced cell cycle arrest and apoptosis. Taken together, the results demonstrated that miR‐206 inhibited the growth of HCC cells through targeting CDK9, suggesting that the miR‐206‐CDK9 pathway may be a novel target for the treatment of HCC.

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Section: Discussionsupporting

confidence: 90%

miR‐206 inhibits the growth of hepatocellular carcinoma cells via targeting CDK9

et al. 2017

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“…A previous study showed that inhibition of CDK2 suppressed PCa metastases by inactivating PI3K/Akt signaling (40). CDK5, CDK6, CDK7, and CDK9 can suppress CRPC through AR inactivation (41)(42)(43)(44). In addition, CDK inhibitors are currently being evaluated in clinical trials (45).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Kinase Expression Related to Increased Migration of PC-3M Cells Using Global Comparative Phosphoproteome Analysis

Gao

Kwon

et al. 2020

Cancer Genomics Proteomics

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Background/Aim: Prostate cancer (PCa) is the second-most commonly occurring cancer among men, worldwide. Although the mechanisms associated with the progression of castration-resistant prostate cancer (CRPC) have been widely studied, the mechanism associated with more distant metastases from the bone remains unknown. This study aimed to characterize potential pathogenic kinases associated with highly metastatic PCa, that may regulate phosphorylation in extensively involved and diverse signaling pathways that are associated with the development of various cancers. Materials and Methods: A mass spectrometry (MS)based comparative phosphoproteome strategy was utilized to identify differentially expressed kinases between the highly aggressive PCa cell-lines PC-3 and PC-3M. Results: Among 2,968 phosphorylation sites in PCa cells, 151 differently expressed phosphoproteins were identified. Seven motifs:-SP- ,-SxxE- ,-PxS- ,-PxSP- ,-SxxK- ,-SPxK-, and-SxxxxxP-were found to be highly expressed in PC-3M cells. Based on these motifs, the kinases p21-activated kinase (PAK)2, Ste20-like kinase (SLK), mammalian Ste20-like kinase (MST)4, mitogenactivated kinase kinase (MAP2K)2, and A-Raf proto-oncogene serine/threonine kinase (ARAF) were up-regulated in PC-3M cells. Conclusion: PAK2, SLK, MST4, MAP2K2, and ARAF are kinases that are potentially associated with the progression of increased migration in PC-3M cells and may represent molecule regulators or drug targets for highly metastatic PCa therapy. Prostate cancer (PCa) is the second-most commonly occurring cancer among men, worldwide (1, 2). According to the latest report by the American Cancer Society, in 2020, 191,930 new cases of PCa will be diagnosed and 33,330 individuals will die from PCa, in the United States (3). Unlike other types of cancers, PCa grows very slowly and may not cause symptoms for years, until the cancer cells metastasize out of the prostate, developing to advanced PCa (4, 5). This characteristic has limited most cases of PCa being recognized and treated during the early stages, and prostate-specific antigen technology began to be applied to the detection of primary-stage PCa in 1994 (6, 7). Because PCa is an androgen-dependent disease (8), androgen deprivation therapy is the standard therapy for the initial stages of advanced PCa; however, treatment can eventually result in the development of castration-resistant PCa (CRPC) (9). Androgen receptor (AR) inhibition remains a key factor in CRPC therapies. Metastatic CRPC (mCRPC) develops when PCa cells spread to other parts of the body, where they can grow and spread, even under medical treatment (10). According to the "seed and soil" theory, proposed by Paget (11), PCa spreads in the bloodstream as "seeds", which settle in specific organs, which represent 543 This article is freely accessible online.

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“…Cyclin-dependent kinase 9 (CDK9) is such a potential target for the treatment of CRC which plays a crucial role in the elongation step of global transcription process. Multiple studies using small molecule inhibitors and RNA interference have demonstrated that oncogenic transcription driven by CDK9 increases the survival and proliferation of cancer cells (Chen et al, 2005;Huang et al, 2014) and hence is continuously targeted for cancer treatment (Baker et al, 2016;Morales and Giordano, 2016;Rahaman et al, 2016). As CDK9 plays such a critical role in the transcription of a number of oncogenes (Krystof et al, 2012;Lam et al, 2001;Wang and Fischer, 2008), targeting CDK9 may provide a promising therapeutic strategy for the treatment of CRC.…”

Section: Introductionmentioning

confidence: 99%

Targeting CDK9 for treatment of colorectal cancer

et al. 2019

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Colorectal cancer (CRC) remains one of the most lethal human malignancies, and pursuit of new therapeutic targets for treatment has been a major research focus. Cyclin‐dependent kinase 9 (CDK9), which plays a crucial role in transcription, has emerged as a target for cancer treatment. CDKI‐73, one of the most potent and pharmacologically superior CDK9 inhibitors, has demonstrated excellent anti‐tumour efficacy against several types of cancers. In this study, we evaluated its therapeutic potential against CRC. CDKI‐73 elicited high cytotoxicity against all colon cancer cell lines tested. Cell cycle and apoptosis analysis in HCT 116 and HT29 cells revealed that CDKI‐73 induced cell death without accumulation of DNA at any phase of the cell cycle. Moreover, it caused depolarisation of mitochondrial membrane, leading to caspase‐independent apoptosis. Knockdown by shRNA demonstrated the CDK9‐targeted mechanism of CDKI‐73, which also affected the Mnk/eIF4E signalling axis. In addition, RT‐qPCR analysis showed that CDKI‐73 down‐regulated multiple pro‐survival factors at the mRNA level. Its in vivo anti‐tumour efficacy was further evaluated in Balb/c nude mice bearing HCT 116 xenograft tumours. CDKI‐73 significantly inhibited tumour growth (***P < 0.001) without overt toxicity. Analysis of the tumour tissues collected from the xenografted animals confirmed that the in vivo anti‐tumour efficacy was associated with CDK9 targeting of CDKI‐73. Overall, this study provides compelling evidence that CDKI‐73 is a promising drug candidate for treating colorectal cancer.

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Targeting CDK9: a promising therapeutic opportunity in prostate cancer

Cited by 60 publications

References 132 publications

miR‐206 inhibits the growth of hepatocellular carcinoma cells via targeting CDK9

miR‐206 inhibits the growth of hepatocellular carcinoma cells via targeting CDK9

Characterization of Kinase Expression Related to Increased Migration of PC-3M Cells Using Global Comparative Phosphoproteome Analysis

Targeting CDK9 for treatment of colorectal cancer

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