Olaparib promotes FABP4 expression and reduces antitumor effect in ovarian cancer cells with a BRCA1 mutation

Wei Huang; Hongxue Meng; Ye Xu; Lan Huang; Ge Lou

doi:10.3892/ol.2024.14813

Olaparib promotes FABP4 expression and reduces antitumor effect in ovarian cancer cells with a BRCA1 mutation

Oncol Lett. 2024 Nov 20;29(2):67. doi: 10.3892/ol.2024.14813. eCollection 2025 Feb.

Authors

Wei Huang¹, Hongxue Meng², Ye Xu¹, Lan Huang³, Ge Lou¹

Affiliations

¹ Department of Gynecological Oncology, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China.
² Department of Pathology, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China.
³ Department of Medical Oncology, Heilongjiang Provincial Hospital, Harbin, Heilongjiang 150000, P.R. China.

Abstract

Olaparib (AZD2281) is used as a first-line maintenance treatment for patients with ovarian cancer (OC) with a breast cancer susceptibility gene (BRCA) mutation. Fatty acid binding protein 4 (FABP4) may serve an important role in cancer, but its role in olaparib-treated OC with a BRCA mutation requires further clarification. To explore the function of FABP4 and enhance the efficacy of AZD2281 in OC, cell counting kit-8, cell apoptosis, cell cycle, colony formation, cell transfection, western blotting, reverse transcription-quantitative polymerase chain reaction, chromatin immunoprecipitation, seahorse and reactive oxygen species assays were performed. In the present study, AZD2281 significantly promoted cell apoptosis, and inhibited cell cycle progression and colony formation in COV362 cells. In addition, AZD2281 significantly upregulated the levels of CCAAT enhancer binding protein α (CEBPα), peroxisome proliferator activated receptor γ (PPARγ) and FABP4. AZD2281 markedly promoted fold enrichment of CEBPα in the promoters of PPARγ and FABP4. Furthermore, FABP4 overexpression significantly decreased cell apoptosis and promoted cell cycle progression and colony formation. In contrast, FABP4 knockdown demonstrated the opposite effects. In addition, FABP4 significantly regulated levels of reactive oxygen species, adenosine triphosphate, aerobic glycolysis, basal respiration rate and fatty acid oxidation. The combination of AZD2281 with the FABP4 inhibitor BM S309403 further significantly increased cell apoptosis and decreased colony formation. In conclusion, the findings of the present study demonstrated that AZD2281 significantly enhanced FABP4 expression, leading to diminished antitumor efficacy in OC cells with a BRCA mutation by regulating CEBPα-PPARγ. Conversely, the combination of AZD2281 and FABP4 inhibitor BM S309403 demonstrated heightened antitumor effectiveness, presenting a promising therapeutic strategy for treating patients with OC with a BRCA mutation.

Keywords: BM S309403; BRCA1 mutation; FABP4; olaparib; ovarian cancer.