Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth

Abstract

Although aerobic glycolysis (the Warburg effect) is a hallmark of cancer, key questions, including when, how, and why cancer cells become highly glycolytic, remain less clear. For a largely unknown regulatory mechanism, a rate-limiting glycolytic enzyme pyruvate kinase M2 (PKM2) isoform is exclusively expressed in embryonic, proliferating, and tumor cells, and plays an essential role in tumor metabolism and growth. Because the receptor tyrosine kinase/PI3K/ AKT/mammalian target of rapamycin (RTK/PI3K/AKT/mTOR) signaling cascade is a frequently altered pathway in cancer, we explored its potential role in cancer metabolism. We identified mTOR as a central activator of the Warburg effect by inducing PKM2 and other glycolytic enzymes under normoxic conditions. PKM2 level was augmented in mouse kidney tumors due to deficiency of tuberous sclerosis complex 2 and consequent mTOR activation, and was reduced in human cancer cells by mTOR suppression. mTOR up-regulation of PKM2 expression was through hypoxia-inducible factor 1α (HIF1α)-mediated transcription activation, and c-Myc-heterogeneous nuclear ribonucleoproteins (hnRNPs)-dependent regulation of PKM2 gene splicing. Disruption of PKM2 suppressed oncogenic mTOR-mediated tumorigenesis. Unlike normal cells, mTOR hyperactive cells were more sensitive to inhibition of mTOR or glycolysis. Dual suppression of mTOR and glycolysis synergistically blunted the proliferation and tumor development of mTOR hyperactive cells. Even though aerobic glycolysis is not required for breach of senescence for immortalization and transformation, the frequently deregulated mTOR signaling during multistep oncogenic processes could contribute to the development of the Warburg effect in many cancers. Components of the mTOR/HIF1α/Myc-hnRNPs/PKM2 glycolysis signaling network could be targeted for the treatment of cancer caused by an aberrant RTK/PI3K/AKT/mTOR signaling pathway.PTEN | tuberous sclerosis 1 | hexokinase II | lactate dehydrogenase-B | glyceraldehyde 3-phosphate dehydrogenase U nlike in normal cells, glycolysis is induced by hypoxia, and cancer cells preferentially metabolize glucose by glycolysis, even in an aerobic environment (1-3). Increased glucose consumption and an elevated rate of lactate production by cancer cells are characteristics of glycolysis, first described by Otto Warburg in the 1920s and thereafter known as the Warburg effect (4). Because this altered metabolism can occur even in the presence of oxygen, glycolysis presumably confers a selective advantage for the survival and proliferation of cancer cells. This catabolic process is, however, inefficient for energy production in that it generates only 2 mol of ATP, instead of an additional 36 mol through the tricarboxylic acid (TCA) cycle, in the presence of oxygen by using 1 mol of glucose (2, 3, 5).Although the Warburg effect is a well-recognized hallmark of cancer metabolism, its regulatory mechanism is still largely obscure. Critical issues, including how and when cancer cells acquire this highly glycolytic phenoty...

Brain-expressed X-linked 2 Is Pivotal for Hyperactive Mechanistic Target of Rapamycin (mTOR)-mediated Tumorigenesis

“…MEFs was subjected to microarray on an Affymetrix GeneChip system with the Affymetrix Mouse Genome 430 2.0 Array, and data were analyzed using the Partek Express software (31).…”

PKM2: A gatekeeper between growth and survival

“…However, an earlier report has indicated that peroxide treatment of cells does result in nuclear localization of PKM2 [5]. This finding also raises the question as to whether the several different post-translational modifications of PKM2 that have been reported, including tyrosyl phosphorylation [1,8], prolyl hydroxylation [9,13], acetylation [14], mono ubiquitination [15], sumoylation [2] and cysteine oxidation [12], are integrated to regulate PKM2's activation of transcriptional programmes [9,10,16] in response to cell signaling events.…”

Deciphering the Key Features of Malignant Tumor Microenvironment for Anti-cancer Therapy

“…This protein causes an increase in glycolysis and the metabolism of glycine, serine, and pyrimidine, promoting stem cell proliferation in several types of cancers. In addition, IDH1 mutants and HMGCR have potential oncogenic activities [51,52]. The mTOR up-regulation of PKM2 through HIF1A-mediated transcriptional activation is important for aerobic glycolysis and tumor growth [53].…”

“…Furthermore, tumor cells produce large quantities of secreted lactate, which causes an acidic environment to stimulate reprogramming gene expression and the genesis of TME [8,[45][46][47][48][49][50][51][52][53][54][55][56][57]. Key genes responsible for abnormal cancer metabolism, such as DGLC and several other aerobic metabolic enzymes, can be targeted using their pharmacological inhibitors in glucose, glutamine, and fatty acid metabolic pathways.…”