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.
Highlights
Ovarian cancer is the most lethal gynecological malignancy in the developed world[1]
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 high grade serous ovarian cancers (HGSOC)
High ABCA1 expression was significantly associated with reduced Progression-free survival (PFS) when only HGSOC was included in the analysis [Table 1B]
Summary
Ovarian cancer is the most lethal gynecological malignancy in the developed world[1]. Epithelial ovarian cancer, which includes serous, clear cell, mucinous and endometrioid subtypes, constitutes 90% of ovarian cancers[2]. Up to 70% of epithelial ovarian cancers are high grade serous ovarian cancers (HGSOC), which are the most common and deadliest ovarian cancer subtype[2]. The initial responses to chemotherapy treatment are high, up to 60% of ovarian cancer patients relapse within six months and 75% of patients become chemoresistant, which is the main factor contributing to ovarian cancer death[2]. The development of more effective therapies for chemotherapy disease is urgently required for improving the survival rate of ovarian cancer patients
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