Molecular mechanisms of cisplatin resistance in cervical cancer

Abstract

Patients with advanced or recurrent cervical cancer have poor prognosis, and their 1-year survival is only 10%-20%. Chemotherapy is considered as the standard treatment for patients with advanced or recurrent cervical cancer, and cisplatin appears to treat the disease effectively. However, resistance to cisplatin may develop, thus substantially compromising the efficacy of cisplatin to treat advanced or recurrent cervical cancer. In this article, we systematically review the recent literature and summarize the recent advances in our understanding of the molecular mechanisms underlying cisplatin resistance in cervical cancer.

Keywords: cisplatin; epithelial-mesenchymal transition; microRNA; molecular mechanism; resistance.

Figure 1

Molecular mechanisms of CPR in cervical cancer. Notes: The molecular mechanisms underlying cisplatin resistance in cervical cancer are complex and associated with the following features: 1) reduction in the intracellular accumulation of the platinum compounds (decrease in uptake, increase in efflux, and increased drug detoxification by cellular thiols); 2) increase in DNA damage repair (increased NER, loss of MMR, and increased TLS); 3) inactivation of apoptosis; 4) activation of EMT; 5) alteration in DNA methylation, microRNA profile, cancer stem cell characteristics, and expression of stress-response chaperones. Abbreviations: CPR, cisplatin resistance; CTR1, copper transporter 1; EMT, epithelial–mesenchymal transition; ERCC1, excision repair cross-complementing; GSH, glutathione; HSC71, heat-shock cognate protein 71; HSP, heat-shock protein; MMR, mismatch repair; MRP1, multidrug resistance protein 1; MSH2, MutS homolog 2; MTs, metallothioneins; NER, nucleotide excision repair; NF-κB, nuclear factor-κB; OCT3, organic cation transporter 3; P-gp, P-glycoprotein; PMS2, post-meiotic segregation 2; TLS, translesion synthesis.

Figure 2

Inactivation of apoptosis pathway and CPR in cervical cancer. Note: Multiple molecules and signaling pathways that inhibit apoptosis can lead to CPR. Abbreviations: CPR, cisplatin resistance; MAPK, mitogen-activated protein kinases; NF-κB, nuclear factor-κB; TNFAIP8, tumor-necrosis-factor-α-induced protein 8.