Novel players in the development of chemoresistance in ovarian cancer: ovarian cancer stem cells, non-coding RNA and nuclear receptors

Abstract

Ovarian cancer (OC) ranks as the fifth leading factor for female mortality globally, with a substantial burden of new cases and mortality recorded annually. Survival rates vary significantly based on the stage of diagnosis, with advanced stages posing significant challenges to treatment. OC is primarily categorized as epithelial, constituting approximately 90% of cases, and correct staging is essential for tailored treatment. The debulking followed by chemotherapy is the prevailing treatment, involving platinum-based drugs in combination with taxanes. However, the efficacy of chemotherapy is hindered by the development of chemoresistance, both acquired during treatment (acquired chemoresistance) and intrinsic to the patient (intrinsic chemoresistance). The emergence of chemoresistance leads to increased mortality rates, with many advanced patients experiencing disease relapse shortly after initial treatment. This review delves into the multifactorial nature of chemoresistance in OC, addressing mechanisms involving transport systems, apoptosis, DNA repair, and ovarian cancer stem cells (OCSCs). While previous research has identified genes associated with these mechanisms, the regulatory roles of non-coding RNA (ncRNA) and nuclear receptors in modulating gene expression to confer chemoresistance have remained poorly understood and underexplored. This comprehensive review aims to shed light on the genes linked to different chemoresistance mechanisms in OC and their intricate regulation by ncRNA and nuclear receptors. Specifically, we examine how these molecular players influence the chemoresistance mechanism. By exploring the interplay between these factors and gene expression regulation, this review seeks to provide a comprehensive mechanism driving chemoresistance in OC.

Keywords: Ovarian cancer; drug resistance; non-coding RNA; nuclear receptor; ovarian cancer stem cells.

Figure 1

(A) Apoptosis modulation to enhance chemoresistance in OC. The increased expression of Bcl-2, MCL-1, Bim, Bcl-XL, IAPs (Survivin, XIAP, &cIAP2), Bax phosphorylation and apoptosis regulation by ubiquitination, galectin, glycosylation, and epigenetic regulation inhibit apoptosis to confer chemoresistance in OC; (B) Increased DNA repair activity to enhance chemoresistance in OC. The aberrant expression of DNA repair genes, i.e., BRCA1/2, RAD51, and its paralogs RAD5IC and RAD5ID, RAD52, MRE11, RIFI, hMLH1, hMSIH2, ERCC1, XPF, RPA1, APE1, and XRCC1, promotes drug resistance in OC. Created with BioRender.com. OC: Ovarian cancer; Bcl-2: B cell lymphoma gene 2; MCL-1: myeloid cell leukemia sequence 1; IAPs: inhibitors of apoptosis proteins; X-linked inhibitor of apoptosis protein; BRCA 1/2: breast cancer gene 1/2; MRE11: meiotic recombination 11; hMLH1: human MutL homolog 1; hMSH2: human MutS homolog 2; ERCC1: excision repair cross-complementation group 1; XPF: xeroderma pigmentosum complementation group F; XRCC1: X-ray repair cross-complementing 1.

Figure 2

(A) Schematic diagram of drug transport in chemoresistance in OC. ABC transporters such as ABCB1, ABCC1, ABCC2, ABCC4, ABCC10, and ABCG2, P-type ATPase ATP7A, and SLC transporter CTR2 responsible for drug efflux are upregulated, while SLC transporter CTR1 that functions for drug influx is downregulated, and P-type ATPase transporter ATP7B does not directly facilitate drug efflux, but its genetic polymorphism can influence drug efflux; (B) OCSCs confer chemoresistance in OC. OSCs are transformed into OCSCs due to genetic alteration, which then proliferate into progenitor cells and subsequently differentiate into cells that contribute to the relapse of ovarian tumors after some time instead of undergoing cell death upon chemotherapy. Created with BioRender.com. OC: Ovarian cancer; ABCB1: ATP-binding cassette subfamily B member 1; ABCC: ATP-binding cassette subfamily C; ABCG2: ATP-binding cassette subfamily G member 2; SLC: solute carrier; CTR1/2: copper transporter 1/2; OCSCs: ovarian cancer stem cells.

Figure 3

(A) Nuclear receptors domain architecture; (B) Diagram illustrating the categorization of nuclear receptors associated with chemoresistance in OC, with a focus on their interaction with ligands; (C) Demonstrating various mechanisms associated with the involvement of nuclear receptors in OC drug^# resistance, primarily encompassing the inhibition of apoptosis, drug efflux, and the presence of OCSCs. Created with BioRender.com. OC: Ovarian cancer; OCSCs: ovarian cancer stem cells.

Figure 4

The well-defined mechanisms associated with various ncRNAs in OC drug^# resistance primarily involve autophagy, drug efflux, inhibiting cell apoptosis, DNA repair, EMT, and OCSCs. Created with BioRender.com and CorelDRAW. ncRNAs: Non-coding RNAs; OC: ovarian cancer; EMT: epithelial to mesenchymal transition; OCSCs: ovarian cancer stem cells.