Targeting Chemoresistant Tumors: Could TRIM Proteins-p53 Axis Be a Possible Answer?

Abstract

Chemosensitivity is a crucial feature for all tumours so that they can be successfully treated, but the huge heterogeneity of these diseases, to be intended both inter- and intra-tumour, makes it a hard-to-win battle. Indeed, this genotypic and phenotypic variety, together with the adaptability of tumours, results in a plethora of chemoresistance acquisition mechanisms strongly affecting the effectiveness of treatments at different levels. Tripartite motif (TRIM) proteins are shown to be involved in some of these mechanisms thanks to their E3-ubiquitin ligase activity, but also to other activities they can exert in several cellular pathways. Undoubtedly, the ability to regulate the stability and activity of the p53 tumour suppressor protein, shared by many of the TRIMs, represents the preeminent link between this protein family and chemoresistance. Indeed, they can modulate p53 degradation, localization and subset of transactivated target genes, shifting the cellular response towards a cytoprotective or cytotoxic reaction to whatever damage induced by therapy, sometimes in a cellular-dependent way. The involvement in other chemoresistance acquisition mechanisms, independent by p53, is known, affecting pivotal processes like PI3K/Akt/NF-κB signalling transduction or Wnt/beta catenin pathway, to name a few. Hence, the inhibition or the enhancement of TRIM proteins functionality could be worth investigating to better understand chemoresistance and as a strategy to increase effectiveness of anticancer therapies.

Metformin inhibits cervical cancer cell proliferation by modulating PI3K/Akt-induced major histocompatibility complex class I-related chain A gene expression

“…P53 protein is mainly distributed in the nucleoplasm of cells and speci cally binds to DNA. Its activity is regulated by post-translational modi cation, such as phosphorylation, acetylation, methylation, and ubiquitination [26,50]. Normal p53 acts as the "guardian of the genome," screening for sites of DNA damage in the G1 phase and monitoring the integrity of the genome.…”

The Tripartite Nexus: Autophagy, Cancer, and Tripartite Motif-Containing Protein Family Members

“…The tumor suppressor protein p53 promotes genomic stability and can induce cell cycle arrest and apoptosis resulting from extensive cellular DNA damage. Interactions between TRIM proteins and p53 are well-established and have recently been reviewed in detail (Valletti et al, 2019). TRIMs 11,21,24,25,28,29,31,32,39, and 59 all negatively regulate p53.…”

“…However, because E3 ubiquitin ligases have some level of specificity in their action, their pharmacological targeting may provide greater therapeutic utility. A prime example of this approach that is currently under investigation is to target interactions between TRIMs and p53, a notable tumor suppressor (Valletti et al, 2019). Inhibiting the E3 ligase activity of these TRIMs to improve p53 stability may represent a selective therapeutic target for cancer.…”

Multifaceted Roles of TRIM Proteins in Colorectal Carcinoma

“…Consistently, overexpression of Mdm2 is frequently observed in early CRC and concomitant with a low p53 abundance [ 85 ]. Alternately to Mdm2, a regulation of p53 by TRIMs has meanwhile been observed in several human malignancies including CRC [ 86 , 87 ]. Without doubt, the regulation of p53 stability and/or activity reported for many TRIM proteins seems to represent the most eminent mechanism through which TRIM can modulate resistance of cancer cells towards chemotherapeutic drugs [ 87 ].…”

“…Alternately to Mdm2, a regulation of p53 by TRIMs has meanwhile been observed in several human malignancies including CRC [ 86 , 87 ]. Without doubt, the regulation of p53 stability and/or activity reported for many TRIM proteins seems to represent the most eminent mechanism through which TRIM can modulate resistance of cancer cells towards chemotherapeutic drugs [ 87 ]. For an up-to-date overview of the role of p53 regulation by TRIMs in tumor chemotherapeutic drug resistance and tumor biology, we refer to reviews by our colleagues [ 86 , 87 ].…”