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.

Keywords: chemo-resistance; gain of function; immune evasion; metabolic reprogramming; oncogenic pathways; p53; stemness.

Figure 1

Frequency of p53 mutations in human cancers. (A) Schematic picture showing the domain structure of the p53 protein, including the transactivation domain, DNA-binding domain and regulatory domain. The aligned graphs indicate the relative frequency of mutations across different domains of p53. p53 mutations are most frequently found in the DNA-binding domain, according to the IARC TP53 database. (B) Percentage frequency of TP53 gene alterations in different types of cancer. The data were obtained from TCGA PanCancer Atlas using a combined study (n = 10,967). (C) Overall survival for human cancer patients (N = 10,953 patients from 32 studies) with mutp53 (red line) or wild type p53 (blue line). The graph was analyzed and obtained from cBioportal.

Figure 2

Canonical functions of wild type p53. Wild type p53 is a major tumor suppressor whose functions are critical for protection against cancer. The canonical functions of wild type p53 include the induction of apoptosis, regulation of oxidative metabolism, and inhibition of glycolytic flux, as well as the response to DNA damage, increased antioxidant capabilities, regulation of immune response and differentiation processes.

Figure 3

Gain-of-function of mutant p53 over proliferation, invasion and metastasis. The principal GOF activities of mutant p53 have nuclear and non-nuclear effects. The nuclear effects involve binding to transcription factors such as HIF-1α or p63 and p73, while the non-nuclear effects are regulation of intracellular proteins, such as RCP, implicated in receptor translocation, DAB2IP scaffold protein implicated in the PI3K/AKT pathway, or SENP1, a protease related to Rac1 activity.

Figure 4

Metabolic reprogramming by mutp53. Mutp53 GOF activities are involved in different critical points of tumor metabolism. Mutp53 favors glucose uptake and hence the Warburg effect through membrane translocation of the glucose transporter, GLUT1, via the RhoA/ROCK1/2 axis. Moreover, mutp53 can induce the Warburg effect by directly inhibiting AMP-activated protein kinase (AMPK), a major cellular energy sensor and a master regulator of metabolic homeostasis. AMPK downregulates fatty acid synthesis by inhibiting transcription factor sterol regulatory element-binding protein 1 (SREBP1). Mutp53 increases the activity of SREBP1, a master regulator of fatty acids and cholesterol biosynthesis, and thus, the mevalonate (MVA) pathway.

Figure 5

Effect of mutp53 over the immune system. Mutp53 supports a pro-inflammatory microenvironment through the release of siL-1RA, CXCL20, CXXCL10, IL-8, or TNF-α, mainly by increasing the transcriptional activity of NF-kB. Additionally, the presence of mutp53 decreases MHC-I expression, avoiding recognition by T cells. Tumor cells can liberate exosomes that act over neighboring macrophages and improve IL-10, MM-9, VNN-1, and TGF-βI release, thus creating a microenvironment that improves cancer progression. Moreover, mutp53 can increase PD-L1, constituting an important mechanism for avoiding the oncolytic activity of T cells.

Figure 6

Relationship of stemness properties with mutp53. Mechanisms related to self-renewal pathways favored by mutp53 include an increased EZH2 (subunit of PCR2 complex) activity and improvement of epigenetic modifications associated with a repressive state of chromatin. Other pathways include YAP/TAZ activity, as well as nuclear effects of FOXH1. Additionally, mutp53 increases CSC markers, such as CD44, CD133, LGR5, and the enzymatic activity of ALDH, contributing to stemness and pharmacological resistance.

Figure 7

Chemoresistance explained by mutp53. The gain-of-function of mutp53 has been broadly implicated in various mechanism of chemoresistance, including resistance to apoptosis, autophagy inhibition, metabolic reprogramming, and increased expression of drug efflux pumps. Additionally, the effect of mutp53 and the downstream effects of gain-of-function favors autophagy inhibition and ROS production, being an important mechanism that explains the overactivation of oncogenic pathways.

Figure 8

Therapeutic approaches targeting mutp53. Therapeutic strategies for treatment of tumors with mutp53 include reestablishing canonical functions of wild type p53, blocking mutp53 GOF, as well as pro-oxidant treatments.