INSERM, N2C UMR 1069, University of Tours, F-37032 Tours, France.
Department of Pathology, CHRU of Tours, CEDEX 9, F-37044 Tours, France.
Int J Mol Sci. 2020 Jul 6;21(13):4786. doi: 10.3390/ijms21134786.
Hypoxia is a well-established feature of prostate cancer (PCa) and is associated with disease aggressiveness. The hypoxic microenvironment initiates multiple adaptive responses including epithelial-to-mesenchymal transition (EMT) and a remodeling of calcium homeostasis involved in cancer progression. In the present study, we identified a new hypoxia signaling pathway with a positive feedback loop between the EMT transcription factor Zeb1 and SK3, a Ca-activated K+ channel, which leads to amplifying store-operated Ca entry. Zeb1 and SK3 channel were strongly upregulated by hypoxia both in vitro and ex vivo in organotypic cultures of human PCa. Taking into account the sensitivity of the SK3 channel to the membrane lipid composition, we identified lipids such as Ohmline (an alkyl ether lipid and SK3 inhibitor), linoleic acid (LA) and eicosapentaenoic acid (EPA) (fatty acids associated with indolent PCa), which were able to completely abrogate the hypoxia-induced changes in Zeb1 expression. Ultimately, better understanding of this new hypoxia-induced EMT pathway may allow to develop adjuvant therapeutic strategies, in order to control PCa aggressiveness and improve treatment outcomes.
缺氧是前列腺癌（PCa）的一个特征，与疾病的侵袭性有关。缺氧微环境会引发多种适应性反应，包括上皮间质转化（EMT）和钙稳态的重塑，这些都与癌症的进展有关。在本研究中，我们发现了一条新的缺氧信号通路，其中 EMT 转录因子 Zeb1 和 Ca 激活的 K+通道 SK3 之间存在正反馈回路，导致储存操作的 Ca 内流放大。在体外和人前列腺癌器官型培养物的离体实验中，缺氧均强烈地上调了 Zeb1 和 SK3 通道的表达。考虑到 SK3 通道对膜脂质组成的敏感性，我们鉴定出了一些脂质，如 Ohmline（一种烷基醚脂质和 SK3 抑制剂）、亚油酸（LA）和二十碳五烯酸（EPA）（与惰性 PCa 相关的脂肪酸），它们能够完全消除缺氧诱导的 Zeb1 表达变化。最终，更好地了解这种新的缺氧诱导的 EMT 通路可能有助于开发辅助治疗策略，以控制 PCa 的侵袭性并改善治疗效果。
