Inactivation of the kinase domain of CDK10 prevents tumor growth in a preclinical model of colorectal cancer, and is accompanied by downregulation of Bcl-2

Louis Bastien Weiswald, Mohammad R. Hasan, John C.T. Wong, Clarissa C. Pasiliao, Mahbuba Rahman, Jianhua Ren, Yaling Yin, Samuel Gusscott, Sophie Vacher, Andrew P. Weng, Hagen F. Kennecke, Ivan Bieche, David F. Schaeffer, Donald T. Yapp, Isabella T. Tai

Research output: Contribution to journalArticle

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Abstract

Cyclin-dependent kinase 10 (CDK10), a CDC2-related kinase, is highly expressed in colorectal cancer. Its role in the pathogenesis of colorectal cancer is unknown. This study examines the function of CDK10 in colorectal cancer, and demonstrates its role in suppressing apoptosis and in promoting tumor growth in vitro and in vivo. Modulation of CDK10 expression in colorectal cancer cell lines demonstrates that CDK10 promotes cell growth, reduces chemosensitivity and inhibits apoptosis by upregulating the expression of Bcl-2. This effect appears to depend on its kinase activity, as kinase-defective mutant colorectal cancer cell lines have an exaggerated apoptotic response and reduced proliferative capacity. In vivo, inhibiting CDK10 in colorectal cancer following intratumoral injections of lentivirus-mediated CDK10 siRNA in a patient-derived xenograft mouse model demonstrated its efficacy in suppressing tumor growth. Furthermore, using a tissue microarray of human colorectal cancer tissues, the potential for CDK10 to be a prognostic biomarker in colorectal cancer was explored. In tumors of individuals with colorectal cancer, high expression of CDK10 correlates with earlier relapse and shorter overall survival. The findings of this study indicate that CDK10 plays a role in the pathogenesis in colorectal cancer and may be a potential therapeutic target for treatment.

Original languageEnglish
Pages (from-to)2292-2303
Number of pages12
JournalMolecular Cancer Therapeutics
Volume16
Issue number10
DOIs
Publication statusPublished - 1 Oct 2017

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Cyclin-Dependent Kinases
Colorectal Neoplasms
Phosphotransferases
Down-Regulation
Growth
Neoplasms
CDC2-CDC28 Kinases
Apoptosis
Cell Line
Lentivirus
Heterografts
Small Interfering RNA
Biomarkers
Recurrence
Injections
Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Inactivation of the kinase domain of CDK10 prevents tumor growth in a preclinical model of colorectal cancer, and is accompanied by downregulation of Bcl-2. / Weiswald, Louis Bastien; Hasan, Mohammad R.; Wong, John C.T.; Pasiliao, Clarissa C.; Rahman, Mahbuba; Ren, Jianhua; Yin, Yaling; Gusscott, Samuel; Vacher, Sophie; Weng, Andrew P.; Kennecke, Hagen F.; Bieche, Ivan; Schaeffer, David F.; Yapp, Donald T.; Tai, Isabella T.

In: Molecular Cancer Therapeutics, Vol. 16, No. 10, 01.10.2017, p. 2292-2303.

Research output: Contribution to journalArticle

Weiswald, LB, Hasan, MR, Wong, JCT, Pasiliao, CC, Rahman, M, Ren, J, Yin, Y, Gusscott, S, Vacher, S, Weng, AP, Kennecke, HF, Bieche, I, Schaeffer, DF, Yapp, DT & Tai, IT 2017, 'Inactivation of the kinase domain of CDK10 prevents tumor growth in a preclinical model of colorectal cancer, and is accompanied by downregulation of Bcl-2', Molecular Cancer Therapeutics, vol. 16, no. 10, pp. 2292-2303. https://doi.org/10.1158/1535-7163.MCT-16-0666
Weiswald, Louis Bastien ; Hasan, Mohammad R. ; Wong, John C.T. ; Pasiliao, Clarissa C. ; Rahman, Mahbuba ; Ren, Jianhua ; Yin, Yaling ; Gusscott, Samuel ; Vacher, Sophie ; Weng, Andrew P. ; Kennecke, Hagen F. ; Bieche, Ivan ; Schaeffer, David F. ; Yapp, Donald T. ; Tai, Isabella T. / Inactivation of the kinase domain of CDK10 prevents tumor growth in a preclinical model of colorectal cancer, and is accompanied by downregulation of Bcl-2. In: Molecular Cancer Therapeutics. 2017 ; Vol. 16, No. 10. pp. 2292-2303.
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