STIM1-dependent Ca2+ signaling regulates podosome formation to facilitate cancer cell invasion

Abstract

The clinical significance of STIM proteins and Orai Ca2+ channels in tumor progression has been demonstrated in different types of cancers. Podosomes are dynamic actin-rich cellular protrusions that facilitate cancer cell invasiveness by degrading extracellular matrix. Whether STIM1-dependent Ca2+ signaling facilitates cancer cell invasion through affecting podosome formation remains unclear. Here we show that the invasive fronts of cancer tissues overexpress STIM1, accompanied by active store-operated Ca2+ entry (SOCE). Interfering SOCE activity by SOCE inhibitors and STIM1 or Orai1 knockdown remarkably affects podosome rosettes formation. Mechanistically, STIM1-silencing significantly alters the podosome rosettes dynamics, shortens the maintenance phase of podosome rosettes and reduces cell invasiveness. The subsequently transient expression of STIM1 cDNA in STIM1-null (STIM1−/−) mouse embryo fibroblasts rescues the suppression of podosome formation, suggesting that STIM1-mediated SOCE activation directly regulates podosome formation. This study uncovers SOCE-mediated Ca2+ microdomain that is the molecular basis for Ca2+ sensitivity controlling podosome formation.

The distinct role of STIM1 and STIM2 in the regulation of store‐operated Ca2+ entry and cellular function

“…To study the clinical relevance of individual ER Ca 2+ sensing STIM protein in tumor progression, the expression patterns of STIM1 and STIM2 were examined in the surgical specimens of early‐stage cervical cancer (Figure ). Consistent with our previous studies (Y. F. Chen et al, ; Y. T. Chen, Chen, Chiu, Liu et al, ; Y. W. Chen et al, ), STIM1 proteins were minimally expressed in noncancerous cervical tissues, but abundant in cervical cancer tissues (Figure a). STIM1 was clearly expressed in the invasive front of cervical carcinoma, an area where squamous cell carcinoma just broke through the basal layers of squamous epithelia (Figure a).…”

“…In contrast, STIM2 exhibited a constitutively aggregated pattern without obvious trafficking or significant association with the microtubule network. These results, combined with our previous studies focusing on STIM1 (Y. F. Chen et al, ; Y. T. Chen, Chen, Chiu, Liu et al, ; Y. T. Chen, Chen, Chiu, Wang et al, ; Y. W. Chen, Chen, Chen et al, ; Y. W. Chen et al, ), define the distinct but cooperative roles for STIM1 and STIM2 that finely tune the intracellular Ca 2+ homeostasis and modulate different aspects of cancer hallmarks.…”

Knockdown of STIM1 expression inhibits non-small-cell lung cancer cell proliferation in vitro and in nude mouse xenografts

“…STIM1, the Ca [2]+ storage sensor protein with a single transmembrane domain localized to the ER, is the key component of SOCE. Also, STIM1 is a key activator of store-operated channels (SOCs) that allow extracellular Ca [2]+ influx into cells [25]. The present study demonstrated that STIM1 was overexpressed in NSCLC tissues and the expression of STIM1 protein was associated with advanced NSCLC T stage.…”

STIM-Orai Channels and Reactive Oxygen Species in the Tumor Microenvironment

“…STIM1-dependent signaling regulates focal adhesion turnover [52,87] required for leading edge protrusion and trailing tail retraction and regulates actomyosin contractility [92]. Furthermore, silencing STIM1 significantly alters podosome dynamics, reduces cell invasiveness [93], and regulates the dephosphorylation of focal adhesion kinase (FAK) by modulating focal adhesion turnover [94,95] and the recruitment and association of active pTyr397-FAK and talin at focal adhesions [92]. Similar results were found in breast cancer cells in a murine tumor metastasis model [87], in colorectal cancer following a destabilization of STIM1 [96], and in glioma cell lines [95].…”