Abstract
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 Ca2+-activated K+ channel, which leads to amplifying store-operated Ca2+ 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.
Highlights
Hypoxia is known to contribute to cancer progression and is associated with resistance to treatment and metastatic dissemination [1]
Human prostate cancer (PCa) cells PC3 were exposed to hypoxia for 24 h or 48 h
Since it was previously reported that KCNN3 is a target gene of Zeb1 [16], we investigated whether the SK3 channel could be regulated by hypoxia
Summary
Hypoxia is known to contribute to cancer progression and is associated with resistance to treatment and metastatic dissemination [1]. Hypoxia leads to epithelial-to-mesenchymal transition (EMT), a process which allows cancer cells to acquire migratory and invasive characteristics, essentials for dissemination and distant metastases [4,5]. Hypoxia has been shown to regulate the expression of EMT markers such as Snail or Zeb1 [6,7,8]. The intracellular signaling pathways that mediate hypoxia-induced EMT remain unclear. Among EMT markers, we previously demonstrated the clinical significance of Zeb in human PCa. its expression is increased according to the different steps of PCa progression and is associated with decreased overall survival [9]. Zeb is a pivotal EMT transcription factor that promotes multidrug resistance, proliferation, and metastasis [4,10]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
