STIM1 accelerates cell senescence in a remodeled microenvironment but enhances the epithelial-to-mesenchymal transition in prostate cancer

Abstract

The importance of store-operated Ca2+ entry (SOCE) and the role of its key molecular regulators, STIM1 and ORAI1, in the development of cancer are emerging. Here, we report an unexpected dual function of SOCE in prostate cancer progression by revealing a decrease in the expression of STIM1 in human hyperplasia and tumor tissues of high histological grade and by demonstrating that STIM1 and ORAI1 inhibit cell growth by arresting the G0/G1 phase and enhancing cell senescence in human prostate cancer cells. In addition, STIM1 and ORAI1 inhibited NF-κB signaling and remodeled the tumor microenvironment by reducing the formation of M2 phenotype macrophages, possibly creating an unfavorable tumor microenvironment and inhibiting cancer development. However, STIM1 also promoted cell migration and the epithelial-to-mesenchymal transition by activating TGF-β, Snail and Wnt/β-Catenin pathways. Thus, our study revealed novel regulatory effects and the mechanisms by which STIM1 affects cell senescence, tumor migration and the tumor microenvironment, revealing that STIM1 has multiple functions in prostate cancer cells.

The store-operated calcium channels in cancer metastasis from cell migration invasion to metastatic colonization

“…The TGFβ-induced EMT was abrogated when STIM1 expression was suppressed with shRNA, suggesting that SOCE is required for TGFβ-mediated EMT (35). The role of SOCE in EMT has also been reported in prostate cancer (99), colon cancer (54) and gastric cancer (97), suggesting that SOCE may regulate cancer metastasis by triggering EMT.…”

A calcium optimum for cytotoxic T lymphocyte and natural killer cell cytotoxicity

“…; Xu et al . ; Hoth, ; Iamshanova et al . ), mutations in Orai channels and other Ca 2+ channels are probably not causally linked to cancer development (Hoth, ).…”

“…In many cancer types changes of expression levels and/or mutations of Orai channels and their activators, stromal interaction molecule (STIM) proteins, have been reported (Chen et al 2011;Bergmeier et al 2013;Vashisht et al 2015). While it is widely believed that Orai channel activity modulates cancer cell growth (Yang et al 2009;Feng et al 2010;Chen et al 2011;Prevarskaya et al 2011;Bergmeier et al 2013;Vashisht et al 2015;Xu et al 2015;Hoth, 2016;Iamshanova et al 2017), mutations in Orai channels and other Ca 2+ channels are probably not causally linked to cancer development (Hoth, 2016). However, considering the prominent role of Orai channels for cytotoxicity of CTLs and NK cells on one hand and for cancer growth on the other hand, Ca 2+ influx through Orai channels has at least a dual role in the tumour microenvironment.…”

STIM and ORAI proteins: crucial roles in hallmarks of cancer

“…Enhanced senescence properties were in fact observed in PC3 cells overexpressing STIM1 or ORAI1, while less senescent cells were detected when knocking down either STIM1 or ORAI1 (107).…”