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Mutant p53 and mTOR/PKM2 regulation in cancer cells
Ilaria Dando1, Marco Cordani1, Massimo Donadelli1
1Department of Neuroscience, Biomedicine and Movement, Biochemistry Section, University of Verona, Verona, Italy.
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. © 2016 IUBMB Life, 68(9):722-726, 2016.
Insights
Mutant TP53 proteins promote cancer by activating mTOR and PKM2 pathways. Inhibiting this axis may offer new therapies for cancers with mutant TP53, enhancing chemoresistance and glycolysis.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- TP53 gene mutations are common in aggressive cancers, leading to loss of tumor suppression and gain-of-function (GOF) oncogenic properties.
- GOF mutant p53 isoforms contribute to chemoresistance, genomic instability, invasiveness, metastasis, and poor patient survival.
- Mammalian target of rapamycin (mTOR) and pyruvate kinase isoform M2 (PKM2) are key regulators of cancer cell growth, metabolism, and proliferation.
Purpose of the Study:
- To investigate the functional pathways regulated by mutant p53.
- To explore the role of the mTOR/PKM2 axis in mutant p53-driven oncogenesis.
- To identify potential therapeutic targets for cancers harboring TP53 mutations.
Main Methods:
- Investigated the interaction between mutant p53 isoforms (R175H, R273H) and the mTOR/PKM2 signaling pathway.
- Assessed the effect of mutant p53 on PKM2 phosphorylation at Tyr 105.
- Utilized molecular and cellular assays to analyze pathway activation and its consequences.
Main Results:
- Gain-of-function (GOF) mutant p53 proteins (R175H, R273H) were found to trigger PKM2 phosphorylation at Tyr 105.
- This phosphorylation is mediated through the involvement of mTOR signaling.
- A novel connection between mutant p53 and mTOR stimulation was established.
Conclusions:
- Mutant p53 activates the mTOR/PKM2 pathway, suggesting a mechanism for its oncogenic activity.
- Inhibiting the mTOR/PKM2 axis presents a potential therapeutic strategy for cancers with mutant TP53.
- This pathway activation may enhance chemoresistance and aerobic glycolysis in cancer cells, contributing to disease progression.
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