Author

Jiaxin Liang

Date of Award

Fall 2018

Document Type

Open Access Dissertation

Department

Pharmacology, Physiology and Neuroscience

First Advisor

Igor Roninson

Abstract

Unresectable hepatic metastases of colon cancer poorly respond to existing therapies and are a major cause of colon cancer lethality. Transcription- regulating Mediator kinase CDK8, an early clinical stage drug target, is amplified or overexpressed in many colon cancers and CDK8 expression correlates with shorter patient survival. Here we show that CDK8 inhibition does not generally suppress proliferation of CDK8-overexpressing colon cancer cells but nevertheless CDK8 knockdown by shRNA or CDK8 kinase inhibition by a selective small-molecule drug candidate suppresses metastatic growth of mouse and human colon cancer cells in the liver. This effect is due at least in part to the inhibition of already established hepatic metastases, indicating therapeutic potential of CDK8 inhibitors in the metastatic setting. In contrast, CDK8 knockdown or inhibition has no significant effect on the growth of tumors implanted subcutaneously, intrasplenically or orthotopically in the cecum. Mechanistically, the site-specific effect of CDK8 on colon cancer growth in the liver is mediated through the downregulation of matrix metalloproteinase (MMP) inhibitor TIMP3 via the TGFβ/SMAD-driven expression of a TIMP3-targeting microRNA, miR-181b, along with the induction of MMP3 in murine or MMP9 in human colon cancer cells via Wnt/β-catenin-driven transcription. These findings reveal a new mechanism for negative regulation of gene expression by CDK8 and a site-specific role for CDK8 in colon cancer hepatic metastasis. Our results indicate potential utility of CDK8 inhibitors for the treatment of colon cancers that metastasized into the liver and suggest that CDK8 inhibitors may be considered in other therapeutic settings involving TGFβ/SMAD or Wnt/β-catenin pathway activation.

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