The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2018

Metabolic Regulation of Stress Response Pathways and Chemoresistance in Colon Cancer is Mediated via B-Raf Dependent Inhibition of PPARγ (#92)

Spencer T Greatorex 1 2 , Joseph Rosenbluh 1 2 , Bethany Campbell 1 2 , Timothy J Cole 1 2
  1. Monash University, Clayton, VIC, Australia
  2. Biochemistry & Molecular Biology, Monash University, Clayton, Victoria, Australia

Colon cancer is the third most common form of cancer and is the second most deadly. Initiator mutations are well characterised with over 70% of colorectal tumours containing APC truncation leading to dysregulated β-catenin signalling. Other mutations including B-Raf and K-Ras are common with more advanced stage tumours and further associated with chemo-resistance via unregulated pro-survival signalling. Other important regulators of proliferation and differentiation in the colon is mediated through PPARG, a master regulator of lipid metabolism. Interestingly, inhibition of PPARG in many cancer models suggest that it plays a role in inhibition of proliferation, while high levels of PPARG transactivation is associated with a well-defined cellular identity. Through use of the TCGA-COAD cancer dataset we have shown dysregulation of crucial PPARG regulated pathways associated with poor cancer prognosis. Furthermore, we have shown that B-Raf is an important negative regulator of PPARG with B-Raf mutants showing resistance to Rosiglitazone mediated cellular cytotoxicity and lipid accumulation. Inhibited lipid partitioning observed in B-raf mutant cells was shown to be normalised through PPARG agonism through an autophagy dependant pathway. Phosphatidylcholine metabolism was shown to be a PPARG regulated pathway and one key enzyme that was shown to be negatively regulated by PPARG was DHRS7B. DHRS7B has been shown to be important in the terminal steps of phosphatidylcholine synthesis while high expression is associated with poor cancer prognosis. DHRS7B overexpression resulted in up-regulation of pro-survival pathways including PI3K/Akt and MAPK, while important stress response genes including cJun and cFos were also shown to be up-regulated. Finally, DHRS7B knockout cells were shown to have decreased cellular growth and were significantly more susceptible to chemotherapy. These results further identify PPARG as a potent tumour suppressor in the colon. Co-treatment of PPARG agonists with commonly used chemotherapy agents promote a significant increase in cell cytotoxicity.