mTORC2 controls cancer cell survival by modulating gluconeogenesis

Abstract

For rapid tumor growth, cancer cells often reprogram the cellular metabolic processes to obtain enhanced anabolic precursors and energy. The molecular changes of such metabolic rewiring are far from established. Here we explored the role of mTOR (mechanistic target of rapamycin), which serves as a key regulator of cell growth, proliferation and survival, in the metabolic reprograming of cancer cells. When we inhibited mTOR in human hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC) cells, using pharmacologic inhibitors or by RNA interference, we noticed shuttle of the glycolytic flux to gluconeogenesis pathway along with reduction in cellular proliferation and survival. Augmentation of gluconeogenesis was mechanistically linked to upregulation of the key gluconeogenic enzymes PCK1 and G6PC expressions, enhanced lactate dehydrogenase activity and glucose-derived lipogenesis without causing any attenuation in mitochondrial function. Interestingly, concomitant knocking down of PCK1 and not G6PC along with mTOR pathway could overcome the inhibition of cancer cell proliferation and survival. These observations were validated by identifying distinctive diminution of PCK1 and G6PC expressions in human HCC and RCC transcriptome data. Significant correlation between mTOR-dependent upregulation of PCK1 and cell death in different cancer cell lines further emphasizes the physiological relevance of this pathway. We reveal for the first time that inhibition of mTORC2 and consequent redistribution of glycolytic flux can have a prosurvival role in HCC and RCC cancer cells only in the presence of downregulation of gluconeogenesis pathway genes, thus identifying novel pivots of cancer cell metabolic rewiring and targets for therapy.

Overexpression of PCK1 Gene Antagonizes Hepatocellular Carcinoma Through the Activation of Gluconeogenesis and Suppression of Glycolysis Pathways

“…The overexpression of PCK1 in two HCC cell lines with relatively lower PCK1 levels inhibited cell viability and migration. Moreover, the antagonizing effect of PCK1 overexpression on HCC cells was concomitant with the suppression of glycolysis and the induction of gluconeogenesis, confirming the conclusion that the promoted gluconeogenesis in HCC would detrimentally affect cancer cell survival [10]. …”

“…The suppression of gluconeogenesis in HCC has been reported by previous studies [9, 10, 20, 21]. Thus, exploring factors activating gluconeogenesis has become a central subject for the development of anti-HCC therapies.…”

“…Numerous studies indicate that the development of neoplasm in livers is always associated with the impaired gluconeogenesis [9, 10]. Thus, the restoration of gluconeogenesis has been proposed as one of the primary tasks for the management of HCC.…”

“…For example, p53 tumor suppressor protein enhanced gluconeogenesis by inducing the expressions of G6PC and PCK2 , which prevented glucose from being shunted to pro-cancer pathways such as glycolysis and pentose phosphate pathway (PPP) [9]. Similarly, the inhibition of mTOR2 in HCC initiated shuttle of the glycolytic flux to gluconeogenesis along with inhibited proliferation and survival in cancer cell, which was also mechanistically linked to the up-regulation of G6PC and PCK1 [10]. …”

“…As a result, two enzymatically indistinct isozymes, PEPCK-C (PCK1) and PEPCK-M (PCK2), encoded by different genes ( PCK1 and PCK2 ) exist [14-16]. Compared with PCK2, PCK1 has been widely studied and is considered as a potential target for the development of novel treating methods for HCC [8, 10, 17]. However, most previous researches explored the function of PCK1 in an indirect way [8, 10, 17], few studies have made attempt to elucidate the role of PCK1 in the development of HCC by directly controlling the expression of the factor.…”