Enhanced Stim1 expression is associated with acquired chemo-resistance of cisplatin in osteosarcoma cells.
Osteosarcoma is the most common primary malignant bone tumor. Although cisplatin is the primary chemotherapy used in osteosarcoma treatment, the cisplatin resistance remains a big challenge for improving overall survival. The store-operated calcium (Ca2+) entry (SOCE) and its major mediator Stim1 have been shown to be implicated in a number of pathological processes typical for cancer. In this study, we showed that Stim1 expression was significantly increased in chemo-resistant osteosarcoma tissues compared with chemo-sensitivity tissues. Patients with Sitm1 expression exhibited poorer overall survival than Stim1-negative patients. Moreover, un-regulation of Stim1 expression and SOCE were also observed in cisplatin-resistant MG63/CDDP cells compared with their parental cells. Cisplatin treatment obviously reduced Stim1 expression and SOCE in cisplatin-sensitivity MG63 cells, but had no effects on MG63/CDDP cells. In addition, cisplatin resulted in a more pronounced increase of endoplasmic reticulum (ER) stress in MG63 cells than in their resistant variants, which was evidenced by the activation of molecular markers of ER stress, GRP78, CHOP and ATF4. Knockdown of Stim1 using siRNA remarkably enhanced cisplatin-induced apoptosis and ER stress in MG63/CDDP cells, thereby sensitizing cancer cells to cisplatin. On the other hand, overexpression of Stim1 markedly reversed apoptosis and ER stress following cisplatin treatment. Taken together, these results demonstrate that Stim1 as well as Ca2+entry contributes cisplatin resistance via inhibition of ER stress-mediated apoptosis, and provide important clues to the mechanisms involved in cisplatin resistance for osteosarcoma treatment. Stim1 represents as a target of cisplatin and blockade of Stim1-mediated Ca2+entry may be a useful strategy to improve the efficacy of cisplatin to treat osteosarcoma.
Department of Orthopaedics, Hebei General Hospital, Shijiazhuang, People's Republic of China.
Xilong
X
Sun
Department of Nuclear Medicine, Hebei General Hospital, Shijiazhuang, People's Republic of China.
Qiang
Q
Wei
Department of Stomatology, Hebei General Hospital, Shijiazhuang, People's Republic of China.
Jie
J
Cheng
Department of Nuclear Medicine, Hebei General Hospital, Shijiazhuang, People's Republic of China.
Yanzhu
Y
Bian
Department of Nuclear Medicine, Hebei General Hospital, Shijiazhuang, People's Republic of China.
Congna
C
Tian
Department of Nuclear Medicine, Hebei General Hospital, Shijiazhuang, People's Republic of China.
Yujing
Y
Hu
Department of Orthopedics, The Third Hospital of Hebei Medical University, No. 139, Ziqiang Road, Qiaoxi District, Shijiazhuang, 050051, Hebei, People's Republic of China. lihj_hebmu@163.com.
Huijie
H
Li
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001859:Bone Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D056726:Genetic Association Studies; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D012516:Osteosarcoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000071737:Stromal Interaction Molecule 1 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D015854:Up-Regulation
D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D009363:Neoplasm Proteins; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D002945:Cisplatin; D002118:Calcium
Apoptosis; Cisplatin resistance; Endoplasmic reticulum; Osteosarcoma; Stim1