The role of insulin signalling via the PI3-kinase/Akt/mTOR pathway and of the anit-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 resu its in poor prognosis, but the underlying mechanisms are still unclcul. We propose that increased circulation of insulin and other growth factors resulls in enhanced signalling through the P13-kinase/AktlmTOR pathway, and in enhanced expression of survival factors, resulting in drug resistance in cancer cells. To this, we are investigating the effect of insulin signalling on Ihe 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 (hal Ihl, is associated with increased Akt phosphorylation, indicative of increased PBK signalling. The PI3K pathway inhibitor Ly294002 prevents the cytoprotective effect of insulin against oxaliplatin-induced cytotoxicity. Activation of PBK kinase/AktlmTOR signalling results in the up-regUlation of survival proteins that are likely involved in the development of anti-cancer drug resistance. The an apopotic tran slationally controlled tumour protein TCTP is a candidate problem to be regulated by the mTOR pathway; its mRNA is highly structured and bears a 5'-TOP signature. We denionstrate that growth-induction ofTCTP is inhibiited 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.