Suppression of STIM1 inhibits human glioblastoma cell proliferation and induces G0/G1 phase arrest

Abstract

BackgroundDepletion of calcium (Ca2+) from the endoplasmic reticulum (ER) activates the ubiquitous store-operated Ca2+ entry (SOCE) pathway which sustains long-term Ca2+ signals and is critical for cellular functions. Stromal interacting molecule 1 (STIM1) serves a dual role as an ER Ca2+ sensor and activator of SOCE. Aberrant expression of STIM1 could be observed in several human cancer cells. However, the role of STIM1 in regulating tumorigenesis of human glioblastoma still remains unclear.MethodsExpression of STIM1 protein in a panel of human glioblastoma cell lines (U251, U87 and U373) in different transformation level were evaluated by Western blot method. STIM1 loss of function was performed on U251 cells, derived from grade IV astrocytomas-glioblastoma multiforme with a lentvirus-mediated short harpin RNA (shRNA) method. The biological impacts after knock down of STIM1 on glioblastoma cells were investigated in vitro and in vivo.ResultsWe discovered that STIM1 protein was expressed in U251, U87 and U373 cells, and especially higher in U251 cells. RNA interference efficiently downregulated the expression of STIM1 in U251 cells at both mRNA and protein levels. Specific downregulation of STIM1 inhibited U251 cell proliferation by inducing cell cycle arrest in G0/G1 phase through regulation of cell cycle-related genes, such as p21Waf1/Cip1, cyclin D1 and cyclin-dependent kinase 4 (CDK4), and the antiproliferative effect of STIM1 silencing was also observed in U251 glioma xenograft tumor model.ConclusionOur findings confirm STIM1 as a rational therapeutic target in human glioblastoma, and also indicate that lentivirus-mediated STIM1 silencing is a promising therapeutic strategy for human glioblastoma.

Cab45S promotes cell proliferation through SERCA2b inhibition and Ca2+ signaling

“…Knockdown of STIM1 inhibits cell proliferation through downregulation of cell cycle genes such as cyclin D1 and cyclin-dependent kinase 4 (CDK4). 49,50 Consistently, our results demonstrate that STIM1 depletion abolishes the Cab45S-dependent cell proliferation. Thus, our data show that, STIM1 is essential for Cab45S-induced cell proliferation mediated by reduction (but not complete depletion) of ER Ca 2+ stores.…”

STIM and ORAI proteins: crucial roles in hallmarks of cancer

“…In contrast, STIM1-mediated Cdc25C expression was regulated at the transcriptional level in cervical cancer cell lines (18). Similar results were observed in glioblastoma cell lines and hypopharyngeal carcinoma where STIM1 silencing inhibited cell proliferation by inducing a cell cycle arrest in G 0 -G 1 with accumulation of p21 and downregulation of cyclin D1 (54,58,95). Moreover, Kim et al (50) reported an increase expression level of ORAI1, but not STIM1 or ORAI3, in RCC: pharmacological inhibition of SOCE or ORAI1 or STIM1 downregulation significantly impaired cell proliferation as well as cell migration of RCC Caki-1 cell lines.…”

STIM1/ORAI1-mediated Ca2+ Influx Regulates Enolase-1 Exteriorization

“…Given the fact that STIM1-and ORAI1-dependent ENO-1 exteriorization markedly contributes to increased breast cancer cell motility, pharmacological blockers of either STIM1 or ORAI1 could represent one possible approach in anti-cancer therapy. Supporting this concept, suppression of STIM1 in the animal model of human glioblastoma significantly inhibited tumor growth and metastasis formation (58).…”

“…Stimulation of STIM1 can activate SOCE, leading to sustained extracellular calcium influx (57). Several studies demonstrated a critical role of STIM1 in cancer cell migration and metastasis formation (58,59). Concomitantly, overexpression of STIM1 has been observed in various types of human cancer, and it was found to have a diagnostic as well as prognostic value (60).…”