Abstract
The TP53 tumor suppressor gene is the most frequently altered gene in tumors and an increasing number of studies highlight that mutant p53 proteins can acquire oncogenic properties, referred to as gain-of-function (GOF). Reactive oxygen species (ROS) play critical roles as intracellular messengers, regulating numerous signaling pathways linked to metabolism and cell growth. Tumor cells frequently display higher ROS levels compared to healthy cells as a result of their increased metabolism as well as serving as an oncogenic agent because of its damaging and mutational properties. Several studies reported that in contrast with the wild type protein, mutant p53 isoforms fail to exert antioxidant activities and rather increase intracellular ROS, driving a pro-tumorigenic survival. These pro-oxidant oncogenic abilities of GOF mutant p53 include signaling and metabolic rewiring, as well as the modulation of critical ROS-related transcription factors and antioxidant systems, which lead ROS unbalance linked to tumor progression. The studies summarized here highlight that GOF mutant p53 isoforms might constitute major targets for selective therapeutic intervention against several types of tumors and that ROS enhancement driven by mutant p53 might represent an “Achilles heel” of cancer cells, suggesting pro-oxidant drugs as a therapeutic approach for cancer patients bearing the mutant TP53 gene.
Highlights
Tumor cells exhibit several metabolic alterations to fulfill the energy needs of uncontrolled growth [1]
We reported that mutant p53 proteins (p53-R175H, p53-R248H, and p53-R273H) were able to repress the transcription of SESN1 and SESN2, and the amount of the SESN/AMPK complex, resulting in the inhibition of AMPK signaling in pancreatic and breast cancer cells [8,89]
Under physiological or low stressing conditions, wild type p53 suppresses reactive oxygen species (ROS) production to inhibit DNA-oxidation, mutagenesis, and oxidative stress-activated signaling pathways involved in cell growth, such as PI3K-Akt and mTOR [64]
Summary
Tumor cells exhibit several metabolic alterations to fulfill the energy needs of uncontrolled growth [1]. Cancer cells expressing mutant p53 show high levels of ROS compared with wild type p53 cells and we and others discovered that GOF mutant p53 isoforms, among the other abilities, contribute to enhance ROS levels in cancer cells through a coordinated regulation of several redox-related enzymes and signaling pathways, favoring cancer cell growth [8]. We summarize the critical role that mutant p53, contrarily to its wild-type counterpart, exerts on ROS production in cancer cells, providing an overview of the discovered molecular mechanisms These observations stress the importance of novel and personalized therapeutic interventions for cancer patients carrying mutant TP53 gene in order to uncover new molecular targets to prevent the GOF mutant p53-driven alterations on cancer energy metabolism, which sustains tumor progression
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