ABCF2, an Nrf2 target gene, contributes to cisplatin resistance in ovarian cancer cells

Abstract

Previously, we have demonstrated that NRF2 plays a key role in mediating cisplatin resistance in ovarian cancer. To further explore the mechanism underlying NRF2-dependent cisplatin resistance, we stably overexpressed or knocked down NRF2 in parental and cisplatin-resistant human ovarian cancer cells, respectively. These two pairs of stable cell lines were then subjected to microarray analysis, where we identified 18 putative NRF2 target genes. Among these genes, ABCF2, a cytosolic member of the ABC superfamily of transporters, has previously been reported to contribute to chemoresistance in clear cell ovarian cancer. A detailed analysis on ABCF2 revealed a functional antioxidant response element (ARE) in its promoter region, establishing ABCF2 as an NRF2 target gene. Next, we investigated the contribution of ABCF2 in NRF2-mediated cisplatin resistance using our stable ovarian cancer cell lines. The NRF2-overexpressing cell line, containing high levels of ABCF2, was more resistant to cisplatin-induced apoptosis compared to its control cell line; whereas the NRF2 knockdown cell line with low levels of ABCF2, was more sensitive to cisplatin treatment than its control cell line. Furthermore, transient overexpression of ABCF2 in the parental cells decreased apoptosis and increased cell viability following cisplatin treatment. Conversely, knockdown of ABCF2 using specific siRNA notably increased apoptosis and decreased cell viability in cisplatin-resistant cells treated with cisplatin. This data indicates that the novel NRF2 target gene, ABCF2, plays a critical role in cisplatin resistance in ovarian cancer, and that targeting ABCF2 may be a new strategy to improve chemotherapeutic efficiency.

The Drug-Resistance Mechanisms of Five Platinum-Based Antitumor Agents

“…Platinum-resistant tumor cells usually have a higher threshold for apoptosis induction, mostly due to the overexpression of anti-apoptotic proteins or the defect in mitochondrial signaling. Many factors contribute to these unwanted phenomenons, such as pro-survival signal pathways (Sun et al, 2016;Bao et al, 2017) [i.e., MAPK/ERK (Kong et al, 2015), PI3K/AKT pathway, NF-kB (Miow et al, 2015)], and tumor microenvironment (TME) and epigenetic regulation (Benard et al, 2014;Ramadoss et al, 2017). Researchers begin focusing on the critical role of non-coding RNA in diverse cellular processes; studies demonstrated that non-coding RNA broadly participated in proapoptotic/antiapoptotic proteins regulation and could work as therapeutic targets or predict markers Zarogoulidis et al, 2015).…”

Emerging role of nuclear factor erythroid 2-related factor 2 in the mechanism of action and resistance to anticancer therapies

“…Several mechanisms are proposed to account for the drug resistance phenotype and many of the genes reported to play roles in drug resistance are identified with a functional link with NRF2 [13] . In anticancer chemotherapy, NRF2 and NRF-dependent genes have been implicated in the cellular resistance to a wide range of anticancer agents (e.g., tamoxifen, Cisplatin, Oxaliplatin, Cisplatin, Doxorubicin, and Etoposide) and cancer types [18][19][20][21][22][23][24][25] . Likewise, the NRF2-centred system and signalling pathway is shown to modulate the action and effectiveness of certain receptor targeted therapies [26][27][28]224,231,232] and potentially promoting cancer resistance to such interventions as Trastuzumab, Pertuzumab, Erlotinib, Lapatinib, imatinib, Gefitinib, Afatinib and Osimertinib.…”

Intrinsic Xenobiotic Resistance of the Intestinal Stem Cell Niche

“…We next examined potential drug resistance pathways, including genes encoding known drug transporters, solute transporters, cytochromes, oxidoreductases, and others (Table S2). Notably, intestinal stromal myofibroblasts had markedly enriched expression of a subset of ATP transporters that serve to efflux a broad range of substrates (Leslie et al, 2005;Vasiliou et al, 2009;Gottesman 2002;Bao et al, 2017) (Figure 4Ai). The most highly enriched and expressed of these were the well-known drug resistance genes, Abcc1 (Mrp1) and Abcb1b (Mdr1b) (Figure 4Aii).…”