BRCA1 affects the resistance and stemness of SKOV3‐derived ovarian cancer stem cells by regulating autophagy

Abstract

Breast cancer 1 (BRCA1) and autophagy both play a significant role in drug resistance. However, little is known about the dynamic cross talk between BRCA1 and autophagy in the regulation of drug sensitivity. Here, we investigated the drug resistance‐associated regulation of BRCA1 in epithelial ovarian cancer stem cells (EOCSCs). The results indicated that BRCA1 could regulate drug resistance in EOCSCs. Autophagy played a significant role in the stemness maintenance and was a key mechanism underlying the survival against chemotherapy in EOCSCs. Further investigation found that BRCA1 could regulate drug resistance of EOCSCs through autophagy. Meanwhile, changes in the level of autophagy provided feedback regarding the expression of BRCA1. Inhibition of autophagy activity could effectively reduce the resistance of EOCSCs caused by BRCA1. In addition, BRCA1 was able to regulate cellular apoptosis and cell cycle progression under the action of cisplatin through autophagy, indirectly affecting the drug sensitivity of EOCSCs. The present results highlight a novel relationship between BRCA1 and autophagy, which may provide insight into the etiology of BRCA1‐associated ovarian cancer, and improve our understanding of resistance mechanisms in ovarian cancer.

Adipocytes induce the resistance of ovarian cancer to carboplatin through ANGPTL4

“…With the improved understanding of ovarian cancer biology, worldwide research has identified several molecular mechanisms regarding the resistance of tumor cells to platinum chemotherapeutics, in particular carboplatin. For example, the overexpression or activation of the mitochondrial enzyme (ATPase in the ABC family) resulted in the reduced intracellular accumulation of platinum drugs ( 19 ); the intracellular nucleophilic molecules can bind with platinum drugs to play a role as the platinum separant ( 20 ); activation of processes, such as nucleotide excision repair ( 21 ), BRCA1/2 mutation ( 22 ) and PMS2 deletion ( 23 ); the formation of epithelial-mesenchymal transition in ovarian cancer cells ( 24 ), autophagy resistance of ovarian cancer cells ( 25 ), and epigenetic changes ( 26 ). Based on this, basic and clinical therapeutic experiments have been performed using westernized medicine combined with platinum drugs.…”

BECN1 and BRCA1 Deficiency Sensitizes Ovarian Cancer to Platinum Therapy and Confers Better Prognosis

“…Interestingly, low expression of BECLIN 1 and of BRCA1 proteins identified platinum-responsive patients, and this was associated with impaired autophagy [ 51 ]. Consistently, BRCA1 deficient ovarian cancer cells were highly dependent on BECLIN 1-dependent autophagy for survival, and rapidly underwent cell death upon autophagy disruption [ 27 , 28 ]. In summary, the present study demonstrates that the concurrent low expression of BECN1 and BRCA1 is sufficient to make ovarian cancer cells more sensitive to chemotherapeutics.…”

“…BRCA2 mutation, but not BRCA1 mutation, was associated with significantly improved overall survival rate [ 26 ]. BRCA1 negatively affects pro-survival autophagy in ovarian cancer cells [ 27 , 28 ].…”

Role of Autophagy in the Maintenance of Stemness in Adult Stem Cells: A Disease-Relevant Mechanism of Action

“…In view of the role of autophagy in the resistance of tumors to chemotherapy, the tumor suppressor gene BRCA1 has been shown to render epithelial ovarian CSCs resistant to cisplatin (a chemotherapeutic drug) by regulating autophagy ( Li D. et al, 2016 ). Autophagy inhibitors may attenuate the drug resistance of epithelial ovarian CSCs mediated by BRCA1 ( You et al, 2019 ). A recent study has also demonstrated that the autophagy inhibitor chloroquine in combination with cisplatin decreases the drug resistance of epithelial cancer cells ( Hwang et al, 2020 ).…”