Central Laboratory, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, China.
Center for Reproductive Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Nutrients. 2022 Sep 14;14(18):3790. doi: 10.3390/nu14183790.
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-κB through EP881C/T-EP266C binding sites. WA supresses the phosphorylation of NF-κB through inhibition of the upstream IKK/IκB phoshorylation to block the expression of ECM1, which reverses the cisplatin-induced activation of NF-κB/ECM1. On the contrary, cisplatin facilitates phosphorylation of NF-κB 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/IκB/NF-κB signaling to reduce the expression of the ECM1 protein.
文替内酯 A（WA）是一种从海洋藻类中分离出来的四环二萜。我们之前发现 WA 抑制癌细胞增殖而毒性很小。在这项研究中，我们发现细胞外基质蛋白 1（ECM1）的高表达促进了癌细胞对顺铂的耐药性，并且分泌的 ECM1 激活正常成纤维细胞（NFs）转化为具有癌相关成纤维细胞（CAFs）特征的细胞。ECM1 基因的转录主要通过 NF-κB 通过 EP881C/T-EP266C 结合位点进行调节。WA 通过抑制 IKK/IκB 磷酸化来抑制 NF-κB 的磷酸化，从而阻断 ECM1 的表达，从而逆转顺铂诱导的 NF-κB/ECM1 的激活。相反，顺铂促进 NF-κB 的磷酸化，从而增强 ECM1 的表达。这些结果突出了 ECM1 作为一种治疗与 ECM1 激活信号相关的顺铂耐药性癌症的潜在靶点。此外，WA 通过 IKK/IκB/NF-κB 信号靶向肿瘤细胞和肿瘤微环境来逆转顺铂耐药性，从而降低 ECM1 蛋白的表达。
