Inhibition of stromal-interacting molecule 1-mediated store-operated Ca(2+) entry as a novel strategy for the treatment of acquired imatinib-resistant gastrointestinal stromal tumors.
Inhibition of stromal-interacting molecule 1-mediated store-operated Ca(2+) entry as a novel strategy for the treatment of acquired imatinib-resistant gastrointestinal stromal tumors.
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抑制基质相互作用分子 1 介导的钙池操纵的 Ca2+ 内流作为治疗获得性伊马替尼耐药胃肠道间质瘤的新策略
DOI：
10.1111/cas.13718
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发表时间：
2018-09
期刊：
影响因子：
5.7
通讯作者：
Dong P
中科院分区：
文献类型：
--
作者：
Yang Z;Pan L;Liu S;Li F;Lv W;Shu Y;Dong P
伊马替尼彻底改变了胃肠道间质瘤（GIST）的治疗；然而，对伊马替尼的原发性和继发性耐药仍然是治疗失败的主要原因。这一进展涉及多种机制。在本研究中，我们报道了一种伊马替尼获得性耐药的新机制，该机制是通过基质相互作用分子 1 (STIM1) 介导的钙池操纵的 Ca2+ 内流 (SOCE) 增强 Ca2+ 内流诱导的。我们发现 STIM1 表达水平与我们研究的队列中对伊马替尼的获得性耐药相关。 STIM1 在伊马替尼耐药 GIST 细胞中的功能也在体内和体外得到证实。结果表明，STIM1 过表达有助于伊马替尼敏感 GIST 细胞的 SOCE 和药物反应。通过 STIM1 敲低来阻断 SOCE 可抑制伊马替尼耐药的 GIST 细胞系和异种移植物的增殖。此外，STIM1介导的SOCE通过MEK/ERK途径发挥抗凋亡作用。这项研究的结果为进一步研究获得性伊马替尼耐药性胃肠道间质瘤的潜在新治疗策略奠定了基础。
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.
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影响因子：
11.5
作者：
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通讯作者：
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影响因子：
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作者：
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