Wang Wanqi, Lokman Noor A, Noye Tannith M, Macpherson Anne M, Oehler Martin K, Ricciardelli Carmela
Adelaide Medical School, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia.
Department of Gynaecological Oncology, Royal Adelaide Hospital, Adelaide, SA 5000, Australia.
Cancer Drug Resist. 2021 Jun 19;4(2):485-502. doi: 10.20517/cdr.2020.107. eCollection 2021.
: 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. : 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 ( = 10) as well as patients with acquired chemotherapy resistance at relapse ( = 6). The effects of the ABCA1 inhibitor apabetalone in carboplatin-sensitive and -resistant cell lines were also investigated. : High mRNA and protein expression was found to be significantly associated with poor patient outcome. mRNA and protein levels were significantly increased in ovarian cancer cell lines (OVCAR-5 CBPR and CaOV3 CBPR) with acquired carboplatin resistance. 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. : These results suggest that inhibiting ABCA1 transporter may be useful in overcoming acquired chemotherapy resistance and improving outcome for patients with HGSOC.
本研究调查了三磷酸腺苷结合盒（ABC）转运蛋白（ABCA1、ABCB1、ABCB3、ABCC2和ABCG2）在高级别浆液性卵巢癌（HGSOC）组织、细胞系和原代细胞中的表达，以确定它们与获得性化疗耐药性及患者预后的潜在关系。分别在公开可用的数据集中以及在诊断时的HGSOC组织芯片（TMA）队列中评估ABC转运蛋白的mRNA和蛋白表达（ABCA1、ABCB1、ABCB3、ABCC2和ABCG2）。还在对化疗敏感的卵巢癌细胞系（OVCAR-5和CaOV3）与获得卡铂耐药性的匹配细胞系以及诊断时患有化疗敏感疾病的患者（n = 10）和复发时获得化疗耐药性的患者（n = 6）的原发性HGSOC细胞中评估ABC转运蛋白的mRNA表达。还研究了ABCA1抑制剂阿巴他龙对卡铂敏感和耐药细胞系的影响。发现高mRNA和蛋白表达与患者预后不良显著相关。在获得卡铂耐药性的卵巢癌细胞系（OVCAR-5 CBPR和CaOV3 CBPR）中，mRNA和蛋白水平显著升高。从获得化疗耐药性的患者获得的原发性HGSOC细胞中，mRNA显著增加。阿巴他龙治疗降低了ABCA1蛋白表达，并增加了亲本和卡铂耐药性卵巢癌细胞对卡铂的敏感性。这些结果表明，抑制ABCA1转运蛋白可能有助于克服获得性化疗耐药性并改善HGSOC患者的预后。
