ABCA1 is associated with the development of acquired chemotherapy resistance and predicts poor ovarian cancer outcome

Wanqi Wang; Noor A Lokman; Tannith M Noye; Anne M Macpherson; Martin K Oehler; Carmela Ricciardelli

doi:10.20517/cdr.2020.107

ABCA1 is associated with the development of acquired chemotherapy resistance and predicts poor ovarian cancer outcome

Cancer Drug Resist. 2021 Jun 19;4(2):485-502. doi: 10.20517/cdr.2020.107. eCollection 2021.

Authors

Wanqi Wang¹, Noor A Lokman¹, Tannith M Noye¹, Anne M Macpherson¹, Martin K Oehler^{1

2}, Carmela Ricciardelli¹

Affiliations

¹ Adelaide Medical School, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia.
² Department of Gynaecological Oncology, Royal Adelaide Hospital, Adelaide, SA 5000, Australia.

Abstract

Aim: This study investigated the ATP binding cassette (ABC) transporter (ABCA1, ABCB1, ABCB3, ABCC2 and ABCG2) expression in high grade serous ovarian cancer (HGSOC) tissues, cell lines and primary cells to determine their potential relationship with acquired chemotherapy resistance and patient outcome. Methods: ABC transporter mRNA and protein expression (ABCA1, ABCB1, ABCB3, ABCC2 and ABCG2) was assessed in publicly available datasets and in a tissue microarray (TMA) cohort of HGSOC at diagnosis, respectively. ABC transporter mRNA expression was also assessed in chemosensitive ovarian cancer cell lines (OVCAR-5 and CaOV3) versus matching cell lines with acquired carboplatin resistance and in primary HGSOC cells from patients with chemosensitive disease at diagnosis (n = 10) as well as patients with acquired chemotherapy resistance at relapse (n = 6). The effects of the ABCA1 inhibitor apabetalone in carboplatin-sensitive and -resistant cell lines were also investigated. Results: High ABCA1 mRNA and protein expression was found to be significantly associated with poor patient outcome. ABCA1 mRNA and protein levels were significantly increased in ovarian cancer cell lines (OVCAR-5 CBPR and CaOV3 CBPR) with acquired carboplatin resistance. ABCA1 mRNA was significantly increased in primary HGSOC cells obtained from patients with acquired chemotherapy resistance. Apabetalone treatment reduced ABCA1 protein expression and increased the sensitivity of both parental and carboplatin-resistant ovarian cancer cells to carboplatin. Conclusion: These results suggest that inhibiting ABCA1 transporter may be useful in overcoming acquired chemotherapy resistance and improving outcome for patients with HGSOC.

Keywords: ABC transporter; ABCA1; ABCB1; ABCB3; ABCC2; ABCG2; HGSOC; TAP2; apabetalone; chemotherapy resistance.