Wentilactone A Reverses the NF-kB/ECM1 Signaling-Induced Cisplatin Resistance through Inhibition of IKK/IkB in Ovarian Cancer Cells

Wentilactone A (WA) is a tetranorditerpenoid isolated from marine algae. We previously found that WA inhibited cancer cell proliferation with little toxicity. In this study, we show that high expression of extracellular matrix protein-1 (ECM1) promotes cancer cell cisplatin resistance, and the secreted ECM1 activates normal fibroblasts (NFs) to transform cells with characteristics of cancer-associated fibroblasts (CAFs). Transcription of the ECM1 gene is regulated largely by NF-kB through EP881C/T-EP266C binding sites. WA supresses the phosphorylation of NF-kB through inhibition of the upstream IKK/IkB phoshorylation to block the expression of ECM1, which reverses the cisplatin-induced activation of NF-kB/ECM1. On the contrary, cisplatin facilitates phosphorylation of NF-kB to enhance the expression of ECM1. These results highlight ECM1 as a potential target for treatment of cisplatin-resistant cancers associated with the ECM1 activated signaling. In addition, WA reverses cisplatin resistance by targeting both tumor cells and the tumor microenvironment through IKK/IkB/NF-kB signaling to reduce the expression of the ECM1 protein.