Orai1 and Stim1 Mediate the Majority of Store-Operated Calcium Entry in Multiple Myeloma and Have Strong Implications for Adverse Prognosis

Abstract

Background/Aims: Multiple myeloma (MM) is a plasma cell neoplasm which constitutes about 10% of all hematologic malignancies. Despite the development and application of novel agents, MM still undergoes an aggressive and incurable course in the vast majority of patients. Ca²⁺ is one of the critical regulators of cell migration. Ca²⁺ influx is essential for the migration of various types of cells including tumor cells. However, the role of store-operated calcium entry (SOC) channels, the only Ca²⁺ channels of non-excitable cells, has not yet been reported in MM cell survival. Methods: We evaluated the expression of Stim1 and Orai1 (two key regulators of SOC) in MM tissues and cell lines by immunohistochemical assay, quantitative real-time PCR assay and western blot. MM cell lines were pretreated with pharmacological blockers and siRNAs, and then MM cell proliferation, cell cycle arrest, and apoptosis were examined by FACS (flow cytometry) assay, and Annexin V-FITC/PI staining. The correlation between the expression of Stim1 (or Orai1) level and outcome in MM were assessed by using Progress Free Survival (PFS). Results: Stim1 and Orai1 were both abundantly expressed in MM tissue and MM cell lines. Inhibition of SOCE reduced MM cell viability, and induced cell cycle arrest and apoptosis. Stim1 or Orai1 silencing also reduced cell viability, caused cell apoptosis and cell cycle arrest in MM cell lines. Over-expression of Stim1/Orai1 in MM patients was closely associated with the clinical outcome of MM. Conclusion: The Stim1/Orai1-mediated signaling participates in the pathogenesis of MM, which represents an attractive target for future therapeutic intervention.

Anti-Cancer Agents in Proliferation and Cell Death: The Calcium Connection

“…Aberrant [Ca 2+ ] i -signaling has been implicated in diseases such as Alzheimer’s, cancer, congestive heart failure, and diabetes [4,5,6]. In cancer, [Ca 2+ ] i -signaling is involved in various processes of tumorigenesis such as proliferation, migration, angiogenesis, and evasion of apoptosis [7,8].…”

“…Moreover, SOC entry controls a wide range of physiological functions such as apoptosis, proliferation, and migration [44]. Significantly, the activation of SOC entry is mediated via internal Ca 2+ -efflux [8]. Ca 2+ stored in the ER and the mitochondria actively contributes to [Ca 2+ ] i -signals as the Ca 2+ influx is triggered by a calcium release from the ER which is mediated through stimulation of surface receptors [45].…”

Store-Operated Ca2+ Entry in Tumor Progression: From Molecular Mechanisms to Clinical Implications

“…Aberrant overexpression of STIM1 or Orai1 and thus upregulated SOCE activity have been observed in several types of human cancers. For instance, STIM1 or Orai1 is overexpressed in tumor tissues when compared with noncancerous or precancerous tissues in patients with breast [29], cervical [24,27,30,31], colorectal [32,33], liver [34], lung [35], clear cell renal cancers [36], or multiple myeloma [37]. Furthermore, the expression of Orai1/STIM1, as well as SOCE activity, is enhanced in cisplatin-resistant ovarian carcinoma cells when compared with the therapy-sensitive parental cells [38].…”

“…The studies in human cervical cancer indicated that STIM1 upregulation in primary tumors was significantly correlated with the poorer clinical outcomes, such as larger tumor size and elevated lymph node metastasis [30]. Overexpression of STIM1/Orai1 in multiple myeloma patients was closely associated with the shorter progression-free survival [37]. In patients with esophageal squamous cell carcinoma, the poorer overall, as well as recurrence-free survival, was characterized by high expression of Orai1 in tumor tissue [40].…”

“…STIM1 or Orai1 silencing in the pancreatic adenocarcinoma Panc1 cells lead to increased apoptosis induced by gemcitabine and 5-fluorouracil [58]—the two common chemotherapy drugs. Similarly, in multiple myeloma cells, inhibition of SOCE or silencing of STIM1 or Orai1 reduced cell viability and caused cell cycle arrest and apoptosis [37]. Interestingly, the antiapoptotic effects of Orai1 were also reported in breast cancer MCF-7 and T47D cells cultured in collagen-coated conditions [59,60].…”