CD147 promotes cisplatin resistance in ovarian cancer by inhibiting FOXM1 degradation via PI3k/Akt-GSK3β pathway

Abstract

Abstract CD147 is a transmembrane glycoprotein that is highly expressed in a number of human cancers, including ovarian cancer. The antibody drug Licartin®, which targets CD147, has been approved by the Chinese Food and Drug Administration (FDA) and entered clinical treatment. Some studies have shown that CD147 plays a role on drug resistance, but the molecular mechanism remains elusive. This study sought to investigate the role and mechanism of CD147 in cisplatin resistance of ovarian cancer. We found that CD147 regulated ubiquitination and degradation of FOXM1 by activating PI3k/Akt-GSK3β pathway in ovarian cancer cells and further regulated the expression of DNA damage repair genes. The CUT&Tag-seq data showed that FOXM1 can directly bind to the promoter regions of several DNA damage repair (DDR) genes such as BRIP1, RRM1, FEN1, RAD50, and PMS2, thereby regulating their transcription. The siRNA against CD147 decreased the expression of FOXM1 and DDR genes, attenuating cisplatin resistance of ovarian cancer in vivo and in vitro experiments. Our results showed a novel cisplatin-resistant mechanism and suggest that the combination of cisplatin with a CD147 suppression is a prospective treatment plan for ovarian cancer that is resistant to cisplatin.