Contribution of the TOR Pathway in Resistance to Common Pharmacological and Chemical Factors

Abstract

The present study evaluated the role of Target of Rapamycin (TOR) signalling pathway in cellular growth resistance to drug or chemical agents. TOR signalling is a master regulator of cellular growth in response to nutrition and stress. The aim of the present study was guided by published reports implicating resistance of pathogens or cancer cells to a wide variety chemicals or pharmacological agents. Studying whether inhibition of TOR signalling could enhance sensitivity or resistance of cells to apoptotic drugs, especially anticancer drugs. TOR signalling is mediated by TOR complex 1 (TORC1) or TORC2. However, fission yeast (Schizosaccharomyces pombe) is suitable model for studying TORC1/2 signalling because it contains two Tor kinases (TOR1 and TOR2) as opposed to a single kinase (TOR1) in mammals. In fission yeast, TOR1, is essential for its survival under stress, accurate cell-cycle arrest at G1 phase. However, its TOR2 counterpart is regulated by TOR1 and therefore, not entirely important. In the present study, wild type (wt.) S. pombe and mutants of TORC1 (tor1 and tco89) were grown on Yeast Extract with Supplements (YES) containing different doses of different TOR inhibitor drugs/chemicals including acetaminophen (APAP; paracetamol), aspirin, ibuprofen, and caffeine. Spot test revealed remarkable growth inhibition in tor1 than tco89 mutants confirming the central role of tor1 in TOR signalling. Ibuprofen did not seem to affect cellular growth indicating that it has no direct effect on TOR signaling pathway. However, ibuprofen-sensitive genes induced significant GO biological process involved in ribonucleoside monophosphate biosynthetic process (7/96) and cellular ketone metabolic processes (6/96). These processes are metabolic in nature and therefore do not diminish cellular growth. Findings from this study have important implications anticancer treatment, ageing and longevity. mTOR inhibitors could enhance the efficacy of cytotoxic anticancer drugs as well as slowdown cellular ageing process to enhance longevity. However, further studies are needed to identify genes that are significantly upregulated during TOR inhibition, and whether they play essential roles in cell-cycle progression or arrest.