The Role of Circular RNAs in the Drug Resistance of Cancers

Abstract

Cancer is a major threat to human health and longevity. Chemotherapy is an effective approach to inhibit cancer cell proliferation, but a growing number of cancer patients are prone to develop resistance to various chemotherapeutics, including platinum, paclitaxel, adriamycin, and 5-fluorouracil, among others. Significant progress has been made in the research and development of chemotherapeutic drugs over the last few decades, including targeted therapy drugs and immune checkpoint inhibitors; however, drug resistance still severely limits the application and efficacy of these drugs in cancer treatment. Recently, emerging studies have emphasized the role of circular RNAs (circRNAs) in the proliferation, migration, invasion, and especially chemoresistance of cancer cells by regulating the expression of related miRNAs and targeted genes. In this review, we comprehensively summarized the potential roles and mechanisms of circRNAs in cancer drug resistance including the efflux of drugs, apoptosis, intervention with the TME (tumor microenvironment), autophagy, and dysfunction of DNA damage repair, among others. Furthermore, we highlighted the potential value of circRNAs as new therapeutic targets and prognostic biomarkers for cancer.

circRNAs in drug resistance of breast cancer

“…The function of some circRNAs in drug resistance of cancers associated with ABC efflux transporters was discovered [14]. In osteosarcoma, the knockdown of circ-CHI3L1.2 down-regulates the expression levels of P-GP, MRP1 and glutathione S-transferase P1 (GSTP1) and has been found to weaken cisplatin (CDDP) resistance [30].…”

“…A potential mechanism of drug resistance mediates the activation of these anti-apoptotic pathways, resulting in the suppression of apoptotic signal transduction. Thus, the mechanism of drug resistance is caused by the emergence of resistance to chemotherapeutics [14]. CircRNAs, which have a highly stable thermodynamic structure, act on and modulate pro-or anti-apoptotic proteins has been stated.…”

“…Their high stability, abundance, and diversity render circRNAs promising biomarkers [130]. With tissue/cell type specificity, aberrant expression, and the association with cancer development and drug resistance in a wide variety of cancers, circRNAs have emerged as possible therapeutic targets over time for overcoming the drug resistance we described above [14,131]. Due to the differential dysregulation of circRNAs in cancer, recent studies have focused on both overexpression and knockdown strategies to target circRNAs.…”

“…Expression levels of circRNAs vary in different cancer types, and altered expression of circRNAs play a vital role in tumor initiation and progression [13]. The role of circRNAs in proliferation, migration, invasion and especially chemoresistance of cancer cells is shown to be displayed through the regulation of the expression of related miRNAs and targeted genes [12,14]. For example, hsa_circ_0000199 is associated with response to chemotherapy by inhibiting phosphatidylinositol-3-kinase/Akt and the mammalian target of rapamycin (PI3K/AKT/mTOR) pathway through miR-613 and miR-206.…”

Exosomal circular RNAs in glioma: coexistence of opportunities and challenges for application

“…CircRNAs delivered by exosomes also made significant contributions to therapeutic resistance in many types of cancers, [ 6 ] including glioma [Figure 1 D].…”