Nrf2 induces cisplatin resistance via suppressing the iron export related gene SLC40A1 in ovarian cancer cells

Abstract

Induction of Nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) has been demonstrated to be involved in cisplatin resistance in ovarian cancer. Solute carrier family 40 member 1 (SLC40A1) is an iron exporter, which possesses many putative Nrf2 binding sites. Here we hypothesize that it may be a possible downstream gene of Nrf2. Elevated level of Nrf2 and reduced level of SLC40A1 were found in cisplatin–resistant ovarian cancer cells as compared with cisplatin-sensitive ovarian cancer cells. Exogenous knockdown of Nrf2 leaded to increased expression of SLC40A1. While overexpression of Nrf2 resulted in decreased expression of SLC40A1. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assay revealed that Nrf2 inhibited the transcription of SLC40A1. Overexpression of SLC40A1 was able to reverse cisplatin resistance induced by Nrf2, while knockdown of SLC40A1 restored cisplatin resistance and increased iron concentration. Desferal, an iron chelator, was found to overcome cisplatin resistance through iron deprivation. Its function was boosted when combined with brusatol, an Nrf2 inhibitor. Taken together, this study first demonstrated that Nrf2 could transcriptionally suppress the expression of SLC40A1. Iron overload induced by SLC40A1 resulted in cisplatin resistance in ovarian cancer. Targeting iron metabolism may be a new therapeutic strategy to reverse drug resistance in ovarian cancer treatment.