Abstract
Simple SummaryThe resistance of neoplastic cells to multiple drugs is a serious problem in cancer chemotherapy. The molecular causes of multidrug resistance in cancer are largely known, but less is known about the mechanisms by which cells deliver phenotypic changes that resist the attack of anticancer drugs. The findings of RNA interference based on microRNAs represented a breakthrough in biology and pointed to the possibility of sensitive and targeted regulation of gene expression at the post-transcriptional level. Such regulation is also involved in the development of multidrug resistance in cancer. The aim of the current paper is to summarize the available knowledge on the role of microRNAs in resistance to multiple cancer drugs.Cancer chemotherapy may induce a multidrug resistance (MDR) phenotype. The development of MDR is based on various molecular causes, of which the following are very common: induction of ABC transporter expression; induction/activation of drug-metabolizing enzymes; alteration of the expression/function of apoptosis-related proteins; changes in cell cycle checkpoints; elevated DNA repair mechanisms. Although these mechanisms of MDR are well described, information on their molecular interaction in overall multidrug resistance is still lacking. MicroRNA (miRNA) expression and subsequent RNA interference are candidates that could be important players in the interplay of MDR mechanisms. The regulation of post-transcriptional processes in the proteosynthetic pathway is considered to be a major function of miRNAs. Due to their complementarity, they are able to bind to target mRNAs, which prevents the mRNAs from interacting effectively with the ribosome, and subsequent degradation of the mRNAs can occur. The aim of this paper is to provide an overview of the possible role of miRNAs in the molecular mechanisms that lead to MDR. The possibility of considering miRNAs as either specific effectors or interesting targets for cancer therapy is also analyzed.
Highlights
In addition to the genotypic causes of cancer, phenotypic impulses play an important role in their etiopathogenesis
The aim of this paper is to provide an overview of the possible role of miRNAs in the molecular mechanisms that lead to multidrug resistance (MDR)
Significant progress has been made in recent decades in understanding the role of miRNAs in the development of multidrug resistance in neoplastic diseases, it is still very difficult to compile a complete summary of the regulatory pathways involved in these events
Summary
In addition to the genotypic causes of cancer, phenotypic impulses play an important role in their etiopathogenesis. Oncogenic miRNA-302s (miRNA-302a-3p, miRNA-302b-3p, and miRNA-302c-3p) are upregulated in NT2-D1 and 833 K tumor germ cell lines, and treatment with cisplatin suppresses this upregulation [91] These miRNAs appear to control the cellular contents of SPRY4-mitogen-activated protein kinase (MAPK) signaling pathway inhibitors, which regulate the MAPK/ERK and PI3K/Akt signaling pathways in these cells. Boyerinas et al [95] found that members of the let-7 family target IMP-1 (insulin-like growth factor mRNA binding protein 1), which prevents translation of mRNA for the P-gp transporter, thereby increasing the sensitivity of cells to its substrates, including Taxol. Mu et al have shown [115] that overproduction of miRNA-27b can increase the sensitivity of cancer cells to a broad spectrum of cytostatics by activating p53-dependent apoptosis and reducing CYP1B1-mediated detoxification. UGT2B4 may be regulated by miRNA135a [141], the authors have not shown an association with drug resistance in cancer cells
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