Mutant p53 as a guardian of the cancer cell

Abstract

Forty years of research have established that the p53 tumor suppressor provides a major barrier to neoplastic transformation and tumor progression by its unique ability to act as an extremely sensitive collector of stress inputs, and to coordinate a complex framework of diverse effector pathways and processes that protect cellular homeostasis and genome stability. Missense mutations in the TP53 gene are extremely widespread in human cancers and give rise to mutant p53 proteins that lose tumor suppressive activities, and some of which exert trans-dominant repression over the wild-type counterpart. Cancer cells acquire selective advantages by retaining mutant forms of the protein, which radically subvert the nature of the p53 pathway by promoting invasion, metastasis and chemoresistance. In this review, we consider available evidence suggesting that mutant p53 proteins can favor cancer cell survival and tumor progression by acting as homeostatic factors that sense and protect cancer cells from transformation-related stress stimuli, including DNA lesions, oxidative and proteotoxic stress, metabolic inbalance, interaction with the tumor microenvironment, and the immune system. These activities of mutant p53 may explain cancer cell addiction to this particular oncogene, and their study may disclose tumor vulnerabilities and synthetic lethalities that could be exploited for hitting tumors bearing missense TP53 mutations.

Fig. 1

Mutant p53 promotes adaptive responses to cancer-related stress conditions to support tumor progression. Cancer cells in a growing tumor are exposed to multiple intrinsic and extrinsic stress conditions. Oncogenic p53 missense mutant forms (mutp53) can sense multiple stress inputs (blue), and act as homeostatic factors to induce adaptive mechanisms (red). Oxidative and proteotoxic stress: mutp53 has been shown to induce a pro-survival response to oxidative stress [45], to facilitate protein folding [69], and to increase proteasome activity [6, 66] in human cancer cell lines of breast, lung, and pancreatic origin. DNA lesions: mutp53 was shown to inhibit the DNA-damage response (DDR) in humanized mutp53 knock-in (HUPKI) mice [48, 49], to counteract autophagic cell death in breast cancer [25], and to inhibit therapy-induced apoptosis in head and neck cancer [55]. Altered metabolic requirements: mutp53 has been shown to sustain anabolic growth by enhancing glucose import and promoting the Warburg effect in mutp53 knock-in mice [34], and to modulate lipid metabolism in human breast cancer cell lines [42]. Hostile tumor microenvironment: mutp53 has been shown to modulate the extracellular milieu by promoting angiogenesis in breast cancer [73, 74], amplifying cancer-promoting inflammation in the colon of knock-in mice [79], and inducing a pro-invasive secretome in human lung tumors and derived cell lines [77]

Fig. 2

The stress adaptive processes induced by mutant p53 trigger positive loops feeding its own accumulation in cancer cells. In tumor cells, the Heat-shock protein (Hsp) chaperone machinery (comprising Hsp90, Hsp70, and Hsp40/DNAJA1) promotes mutp53 stabilization by inhibiting the ubiquitin ligases MDM2 and CHIP; mutant p53 can further enhance this mechanism by different means. In breast cancer cells, mutp53 was shown to induce the mevalonate pathway in concert with SREBP [42], thereby producing M5P that promotes interaction of mutp53 with Hsp40/DNAJA1 [44], as well as GGPP that stimulates RhoA activation and cancer cell mechano-responsiveness. In multiple tumor-derived cell lines, mutp53 was shown to promote RhoA activation also by inducing its positive regulators GEF-H1 [23] and RhoGDI [24]. Mechano-transduction activates the Hsp90 cofactor HDAC6, and this was shown to boost mutp53 stabilization in breast cancer cell lines and tumor xenografts [19]. Finally, in human and mouse breast cancer cell lines, mutp53 was shown to directly upregulate Hsp90/Hsp70 expression by stimulating HSF1 activity [14]. Besides the ubiquitin-proteasome pathway, mutp53 is degraded by autophagy-mediated proteolysis upon glucose deprivation [25]; in breast cancer models, mutp53 was shown to counteract the autophagic process [25]. Moreover, in various human cancer cell lines and in mutp53 knock-in mice, mutp53 was shown to increase intracellular glucose levels by stimulating RhoA-dependent membrane translocation of the Glut1 transporter [34]. M5P mevalonate-5-phosphate; GGPP geranylgeranyl-pyrophosphate

Fig. 3

Mutant p53 facilitates adaptation to proteotoxic stress by multiple mechanisms. a In breast cancer cell lines, it was shown that mutp53 cooperates with NRF2 to induce expression of multiple proteasome subunits, accelerating turnover of tumor-suppressor proteins [66]. At the same time, increased proteasome activity contributes to alleviate stress caused by accumulation of misfolded proteins. b In pancreatic and breast cancer cell lines, it was shown that mutp53 cooperates with Sp1 to induce expression of ENTPD5, an enzyme involved in quality control of N-glycosylated secreted and membrane proteins, enhancing production of growth factors and growth-factor receptors [69]. At the same time, ENTPD5 may favor protein folding in the ER, and promote secretion. c Finally, in human and mouse breast cancer cell lines, it was shown that mutp53 cooperates with HSF1 to induce expression of various Hsp chaperones, contributing to alleviate proteotoxic stress, at the same time promoting mutp53 stabilization [14]

Fig. 4

A schematic view of therapeutic opportunities targeting mutp53 and the homeostatic mechanisms it coordinates in cancer cells. Cancer cell addiction to mutp53-dependent stress support mechanisms can be exploited for therapeutic purposes by implementing pharmacologic strategies aimed at disrupting the balance of pro- and anti-survival signaling, in combination with molecules that directly target mutp53 and/or the mechanisms leading to its cancer-specific activation. PRIMA-1 is paradigmatic of small molecule compounds restoring mutp53 to its wild-type conformation and leading to its degradation. Destabilization of mutp53 by inhibition of the Heat-shock protein (Hsp) chaperone machinery can be obtained by different compounds, including inhibitors of Hsp90-Hsp40 and HDAC inhibitors (SAHA). Molecules inhibiting different steps of the Mevalonate-RhoA axis, including statins, Zoledronic Acid (ZA) and geranylgeranyl-transferase inhibitors (GGTI) can indirectly block Hsp90 activation and mutp53 stabilization, also blunting other oncogenic effects of this metabolic axis. Similarly, Pin1 inhibitors such as ATRA/ATO and KPT-6566 prevent mutp53 oncogenic activation in tumor cells. Metformin could block glucose-dependent mutp53 stabilization, and mTOR inibitors such as Everolimus curb tumor cell survival. Therapeutic approaches can be aimed to inhibit the stress support pathways sustained by mutp53 (sensitization), or to exacerbate stress conditions to overcome stress support pathways (stress overload). E.g. proteasome inhibitors blunt a major proteotoxic stress response pathway; inhibitors of the thioredoxin system (e.g. Auranofin) block antioxidant mechanisms; DDR kinase inhibitors and PARP inhibitors prevent responses to genotoxic stress; PRIMA-1 and the Pin1 inhibitor KPT-6566 increase ROS levels in cancer cells