The role of insulin signalling via the PI3-kinase/Akt/mTOR pathway and of the anti-apoptotic translationally controlled tumour protein TCTP in the development of drug resistance in colon cancer cells

Obesity is closely associated with colon cancer; it increases its incidence and results in poor prognosis, but the underlying mechanisms are still unclear. We propose that increased circulation of insulin and other growth factors results in enhanced signalling through the PI3-kinase/Akt/mTOR pathway, and in enhanced expression of survival factors, resulting in drug resistance in cancer cells. To test this, we are investigating the effect of insulin signalling on the expression of cell survival proteins, such as TCTP, in HT29 colon cancer cells. We show that insulin reverses the cytotoxic effect of oxaliplatin on HT29 cells, and that this is associated with increased Akt phosphorylation, indicative of increased PI3K signalling. The PI3K pathway inhibitor Ly294002 prevents the cytoprotective effect of insulin against oxaliplatin-induced cytotoxicity. Activation of PI3-kinase/Akt/mTOR signalling results in the up-regulation of survival proteins that are likely involved in the development of anti-cancer drug resistance. The anti-apopotic translationally controlled tumour protein TCTP is a candidate protein to be regulated by the mTOR pathway; its mRNA is highly structured and bears a 5'-TOP signature. We demonstrate that growth-induction of TCTP is inhibited in the presence of rapamycin. We are currently investigating whether TCTP is upregulated in response to enhanced insulin signalling in HT29 colon cancer cells and whether it confers anti-cancer drug resistance to these cells.