Mutant p53 Gain-of-Function: Role in Cancer Development, Progression, and Therapeutic Approaches

Abstract

Frequent p53 mutations (mutp53) not only abolish tumor suppressor capacities but confer various gain-of-function (GOF) activities that impacts molecules and pathways now regarded as central for tumor development and progression. Although the complete impact of GOF is still far from being fully understood, the effects on proliferation, migration, metabolic reprogramming, and immune evasion, among others, certainly constitute major driving forces for human tumors harboring them. In this review we discuss major molecular mechanisms driven by mutp53 GOF. We present novel mechanistic insights on their effects over key functional molecules and processes involved in cancer. We analyze new mechanistic insights impacting processes such as immune system evasion, metabolic reprogramming, and stemness. In particular, the increased lipogenic activity through the mevalonate pathway (MVA) and the alteration of metabolic homeostasis due to interactions between mutp53 and AMP-activated protein kinase (AMPK) and Sterol regulatory element-binding protein 1 (SREBP1) that impact anabolic pathways and favor metabolic reprograming. We address, in detail, the impact of mutp53 over metabolic reprogramming and the Warburg effect observed in cancer cells as a consequence, not only of loss-of-function of p53, but rather as an effect of GOF that is crucial for the imbalance between glycolysis and oxidative phosphorylation. Additionally, transcriptional activation of new targets, resulting from interaction of mutp53 with NF-kB, HIF-1α, or SREBP1, are presented and discussed. Finally, we discuss perspectives for targeting molecules and pathways involved in chemo-resistance of tumor cells resulting from mutp53 GOF. We discuss and stress the fact that the status of p53 currently constitutes one of the most relevant criteria to understand the role of autophagy as a survival mechanism in cancer, and propose new therapeutic approaches that could promote the reduction of GOF effects exercised by mutp53 in cancer.

Potentiating Therapeutic Effects of Epidermal Growth Factor Receptor Inhibition in Triple-Negative Breast Cancer

“…Mutations of the tumor suppressor p53 are well established as being associated with approximately 50% of human cancers [ 235 , 236 , 237 , 238 , 239 ]. A panel of TNBC cell lines has been identified to express mutant p53 (mtp53) [ 240 ], which is commonly found in TNBC [ 120 , 192 ].…”

“…As mentioned earlier, p53 mutations are commonly found in TNBC [ 120 , 192 ]. Since p53 mutations result in gain-of-function as an oncogene as well as loss-of-function in terms of tumor suppressor function, targeting mtp53 or restoring wild-type p53 (wtp53) is a promising therapeutic option [ 239 ]. Notably, adenoviral-vector-expressing wtp53 (Ad-wtp53) was approved as the world’s first commercial gene therapy product by the Chinese regulatory authority [ 581 ].…”

Relationship between p53 status and the bioeffect of ionizing radiation (Review)

“…p53 mt deactivates sequence-specific DNA-binding activity, thereby causing the loss of normal p53 tumor suppressor function and the inability of the p53 wt heterodimer to form a tetramer complex, thereby damaging dimer function ( 22 ). In addition, p53 mt causes another ‘gain of function’ (GOF) that not only promotes tumor progression, migration and metabolism but also increases tumor cell resistance to radiotherapy ( 23 , 24 ). This outcome is ascribed to the upregulation of multiple genes by p53 mt , including phosphatase and tensin homolog, c-myc, NF-κB, p16 INK4A , p63 and p73 ( 25 – 30 ).…”

The Landmark Discovery That Paved the Way to a Mechanistic Understanding of P53 Gain of Function and Personalized Medicine

“…This crucial observation was made by analyzing the TP53 locus in a series of 25 adenomas and 33 colorectal carcinomas. The authors' strategy comprised both the quantification of allelic deletions occurring in this locus and the sequencing of its exons 5 to 9, which correspond to its DNA-binding domain, where the vast majority of p53 mutations cluster in human cancers (3). Through these analyses, the authors found that in 90% of adenomas, both TP53 alleles were retained and did not have any mutations.…”

“…The answer, the authors argued, must be that the mutation of TP53-rather than its simple loss-endows cancer cells with advantageous properties allowing tumors to become invasive. This was formally proven to be correct in 2004, when two laboratories led by Guillermina Lozano (4) and Tyler Jacks (5) generated mouse models mimicking the Li-Fraumeni syndrome, a disease caused by the somatic mutation of TP53 predisposing to the spontaneous onset of multiple tumor types, especially in children and young adults (3). Importantly, in contrast to Trp53 À/À mice, both Trp53 R172H/À and Trp53 R270H/À mice developed distinct tumors, including invasive and metastatic carcinomas (4, 5), thus confirming the hypothesis based on analysis of clinical samples.…”