Inhibition of stromal‐interacting molecule 1‐mediated store‐operated Ca²⁺ entry as a novel strategy for the treatment of acquired imatinib‐resistant gastrointestinal stromal tumors

Abstract

Imatinib has revolutionized the treatment of gastrointestinal stromal tumors (GIST); however, primary and secondary resistance to imatinib is still a major cause of treatment failure. Multiple mechanisms are involved in this progression. In the present study, we reported a novel mechanism for the acquired resistance to imatinib, which was induced by enhanced Ca2+ influx via stromal‐interacting molecule 1 (STIM1)‐mediated store‐operated Ca2+ entry (SOCE). We found that the STIM1 expression level was related to the acquired resistance to imatinib in our studied cohort. The function of STIM1 in imatinib‐resistant GIST cells was also confirmed both in vivo and in vitro. The results showed that STIM1 overexpression contributed to SOCE and drug response in imatinib‐sensitive GIST cells. Blockage of SOCE by STIM1 knockdown suppressed the proliferation of imatinib‐resistant GIST cell lines and xenografts. In addition, STIM1‐mediated SOCE exerted an antiapoptotic effect via the MEK/ERK pathway. The results from this study provide a basis for further research into potential novel therapeutic strategies in acquired imatinib‐resistant GIST.

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

“…Additionally, inhibition of SOC activity by non-steroidal anti-inflammatory drugs (NSAIDs) attenuated proliferation in the HRT-18 colon cancer cell line [51]. As the SOC entry is considered to be primary Ca 2+ entry mechanism in most cancer types (thus contributing to cancer cell migration, invasiveness, and metastasis), there is a high interest in development of selective SOC entry blockers to prevent cancer metastasis [52,53].…”

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

“…Moreover, patients with positive STIM1 expression exhibited a poorer overall survival than those with negative STIM1 expression. A recent study in gastrointestinal stromal tumors showed that STIM1-dependent SOCE activation contributes to resistance against imatinib, a small molecule kinase inhibitor, though the MEK/ERK pathway [69]. A vital role for STIM1/Orai1-mediated SOCE in resistance against rituximab, the anti-CD20 monoclonal antibody used for treating B-cell malignancies, has also been demonstrated [70].…”

A high-concentrate diet provokes inflammation, endoplasmic reticulum stress, and apoptosis in mammary tissue of dairy cows through the upregulation of STIM1/ORAI1

“…The influx of extracellular Ca 2+ can disrupt intracellular homeostasis, leading to intracellular calcium overload, which results in apoptosis (Pinton et al, 2001;Targos et al, 2005). Previous studies have shown that STIM1-mediated SOCE can promote the apoptosis of tumor cells by inducing calcium flow (Yang et al, 2018) and that hyperglycemia induces apoptosis in human umbilical vein epithelial cells through SOCE (Tamareille et al, 2006). Previous research has also reported that extracellular Ca 2+ influx, which is mediated by SOCE in a STIM1-dependent manner, is involved in NaB-induced apoptosis in colon cancer cells (Sun et al, 2012).…”