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.
Highlights
Chemotherapeutic agents have become widely applied for the treatment of various types of malignancies
On-target resistance to cisplatin is not linked to alteration of DNA but to impaired recognition of cisplatin-induced lesions, increasing tolerance to them or the ability to repair them [20]. These last two chemoresistance mechanisms, in particular, may be induced in different ways: (i) increasing directly the expression of DNA repair proteins (e.g., high expression of O6-methylguanine-DNA-methyltransferase (MGMT), involved in direct reversal repair, is associated with resistance to alkylating agents, in particular temozolomide [21]); (ii) over-expressing growth factor receptors, such as epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF1R), whose signalling pathways are involved in promoting different DNA repair mechanisms [22,23]
Resistance to chemotherapy can arise when anti-apoptotic proteins, such as anti-apoptotic BCL-2 family members, inhibitors of apoptosis proteins (IAPs) and the caspase 8 inhibitor CASP8 and FADD like apoptosis regulator (CFLAR alias FLIP), undergo gain-of-function mutations or amplification or are overexpressed [25,26]. These genes may be transcriptional targets for pro-survival transcription factors, for example nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3), whose expression is frequently activated during tumorigenesis [25]
Summary
Chemotherapeutic agents have become widely applied for the treatment of various types of malignancies. Cancer cells sometimes fail to respond to a specific chemotherapeutic regimen because of the presence of inherently resistant cells that harbour pre-existing random mutations, which are selected for This is called “intrinsic resistance”, and is usually linked to processes involved in tumorigenesis itself [1]. Cancer cells can acquire drug resistance throughout the treatment (i.e., “acquired resistance”), and this is possibly the most important factor that determines success or failure in cancer therapy [1] This unwanted side outcome of drug treatment is extremely multifactorial and, albeit several mechanisms have been described in different tumours, research is still trying to understand if this is a selective process (like intrinsic resistance) or a non-genetic adaptive one (or probably a combination of both) [2,3]. Other p53-independent mechanisms and the therapeutic potential of TRIM proteins for cancer therapy will be discussed in the last part of this review
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