Mutant p53 and mTOR/PKM2 regulation in cancer cells

Abstract

Mutations of TP53 gene are the most common feature in aggressive malignant cells. In addition to the loss of the tumor suppressive role of wild-type p53, hotspot mutant p53 isoforms display oncogenic proprieties notoriously referred as gain of functions (GOFs) which result in chemoresistance to therapies, genomic instability, aberrant deregulation of cell cycle progression, invasiveness and enhanced metastatic potential, and finally, in patient poor survival rate. The identification of novel functional oncogenic pathways regulated by mutant p53 represent and intriguing topic for emerging therapies against a broad spectrum of cancer types bearing mutant TP53 gene. Mammalian target of rapamycin (mTOR), as well as pyruvate kinase isoform M2 (PKM2) are master regulators of cancer growth, metabolism, and cell proliferation. Herein, we report that GOF mutant R175H and R273H p53 proteins trigger PKM2 phosphorylation on Tyr 105 through the involvement of mTOR signaling. Our data, together with the newly discovered connection between mutant p53 and mTOR stimulation, raise important implications for the potential therapeutic use of synthetic drugs inhibiting mTOR/PKM2 axis in cancer cells bearing mutant TP53 gene. We further hypothesize that mTOR/PKM2 pathway stimulation serves to sustain the oncogenic activity of mutant p53 through both the enhancement of chemoresistance and of aerobic glycolysis of cancer cells. V C 2016 IUBMB Life, 68(9): [722][723][724][725][726] 2016

TRRAP is essential for regulating the accumulation of mutant and wild-type p53 in lymphoma

“…Several lines of evidence support a specific link between TRRAP and p53 regulation and function. First, other members of the PIKK family (ATM, 54,55 ATR, 56,57 DNA-PKcs, 58,59 SMG1, 60,61 and mTOR 62,63 ) are either direct regulators of p53 or are under the control of p53. Secondly, TRRAP has been reported to bind to wtp53 and to be essential for wtp53-dependent MDM2 expression.…”

Mutant p53-Associated Molecular Mechanisms of ROS Regulation in Cancer Cells

“…One of the activator of HIF1 is the M2 isoform of pyruvate kinase (PKM2) [119]. We showed that mutant p53 induces PKM2 in a mTOR-dependent manner [121]. Since PKM2 supports anabolic metabolism and PKM2 and is a crucial metabolic enzyme in the oncogenic mTOR-induced glycolysis [122], we hypothesized that mTOR/PKM2 pathway might contribute to the metabolic alterations in cancer cells bearing mutant TP53 gene.…”

“…These studies support the existence of different mechanisms induced by mutant p53 proteins to modulate the expression of secreted inflammatory cytokines in order to sustain an inflammatory tumor microenvironment, thus potentially contributing to promote oxidative stress and increased cancer aggressiveness. [110,117,118,120,121] R175H, R248W, R273H NF-kB Lung, pancreatic, breast and colon cancer [158][159][160][161][162] R175H, R281G, R273H Cytokines Lung, breast, pancreatic and colon cancer [157,164,165] R175H, R273H PGC1-α Lung, colon and pancreatic cancer [8,137] R175H, R280K, R273H NRF2 Colon carcinoma, oesophageal adenocarcinoma, lung and breast cancer [133][134][135] R175H, R273H AMPK Pancreatic and breast cancer [8,89,110] R175H, R248H, R273H SESNs Breast and pancreatic cancer [8,89] R175H, R273H UCP2 Lung, pancreatic and breast cancer [8] R175H, R273H GSH Oesophageal adenocarcinoma, pancreatic and breast cancer [128,135] R175H, R273H Autophagy Lung carcinoma, pancreatic and breast cancer [89]…”

Molecularly targeted therapies for p53-mutant cancers

“…Previous studies showed that genomic stress can induce autophagy in a p53-dependent fashion and wild-type p53 can activate autophagy by upregulating autophagy-related gene DRAM1 (damage-regulated autophagy modulator 1) (135). However, several line of recent studies demonstrated that specific p53 mutants (R175H, R273H, R273L) that localize in the cytoplasmic can gain new function to inhibit autophagy either through blockade of AMPK signaling or activation of Akt/mTOR signaling (136, 137). In contrast, other p53 mutants (P151H, R282W) that localize in the nucleus failed to inhibit autophagy (138).…”