Phosphoinositide‐3‐kinase pathway stringently controls cellular status of pyruvate kinase M2 to determine cancer metabolism

Abstract

Growth factors signaling (GF) play a vital role in promoting anabolism in cancer cells, allowing them to grow and divide efficiently. However, it is not clear how GF contributes to this metabolic transformation. In this study we are reporting a mechanism that allows GF signaling to promote anabolism. As it has been shown recently that expression of pyruvate kinase M2 (PKM2) is central to cancer metabolism, we investigated the effect of inhibiting major GF transducers, Phosphoinositide 3‐kinase pathway (PI3K), Mammalian target of rapamycin (mTOR) and Mitogen activated protein kinase (MAPK) on cellular status of key enzyme PKM2. We observed down regulation of PKM2 expression and activity on mTOR and MAPK inhibition. Surprisingly, on PI3K inhibition ~25% increase in PKM2 activity was observed despite reduced expression of PKM2. The peculiar effect of PI3K inhibition on PKM2 activity was due to shift in crucial PKM2 Dimer/Tetramer (D/T) equilibrium in favor of highly active tetramer. We further investigated the implication of shifted D/T equilibrium on metabolism by LC‐MS, which interestingly showed substantial reduction in intracellular levels of anabolic markers, ribose‐5‐phosphate and lactate, indicating the suppression of cancer metabolism. The study depicts the unique potential of PI3K pathway in affecting cancer metabolism via PKM2 oligomeric state, hence widening the window of therapeutic interventions in cancer. Moreover, our results correlate with the recent reports that PI3K pathway is the most frequently mutated/dysregulated pathway in cancer. We acknowledge UGC, Govt. of India, for research funds.