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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 (Ca(2+)) entry (SOCE) and its major mediator Stim1...

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Autores principales: Sun, Xilong, Wei, Qiang, Cheng, Jie, Bian, Yanzhu, Tian, Congna, Hu, Yujing, Li, Huijie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Japan 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486860/
https://www.ncbi.nlm.nih.gov/pubmed/28326487
http://dx.doi.org/10.1007/s13577-017-0167-9
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author Sun, Xilong
Wei, Qiang
Cheng, Jie
Bian, Yanzhu
Tian, Congna
Hu, Yujing
Li, Huijie
author_facet Sun, Xilong
Wei, Qiang
Cheng, Jie
Bian, Yanzhu
Tian, Congna
Hu, Yujing
Li, Huijie
author_sort Sun, Xilong
collection PubMed
description 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 (Ca(2+)) 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 Ca(2+) 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 Ca(2+) entry may be a useful strategy to improve the efficacy of cisplatin to treat osteosarcoma. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s13577-017-0167-9) contains supplementary material, which is available to authorized users.
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spelling pubmed-54868602017-07-17 Enhanced Stim1 expression is associated with acquired chemo-resistance of cisplatin in osteosarcoma cells Sun, Xilong Wei, Qiang Cheng, Jie Bian, Yanzhu Tian, Congna Hu, Yujing Li, Huijie Hum Cell Research Article 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 (Ca(2+)) 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 Ca(2+) 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 Ca(2+) entry may be a useful strategy to improve the efficacy of cisplatin to treat osteosarcoma. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s13577-017-0167-9) contains supplementary material, which is available to authorized users. Springer Japan 2017-03-22 2017 /pmc/articles/PMC5486860/ /pubmed/28326487 http://dx.doi.org/10.1007/s13577-017-0167-9 Text en © The Author(s) 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Research Article
Sun, Xilong
Wei, Qiang
Cheng, Jie
Bian, Yanzhu
Tian, Congna
Hu, Yujing
Li, Huijie
Enhanced Stim1 expression is associated with acquired chemo-resistance of cisplatin in osteosarcoma cells
title Enhanced Stim1 expression is associated with acquired chemo-resistance of cisplatin in osteosarcoma cells
title_full Enhanced Stim1 expression is associated with acquired chemo-resistance of cisplatin in osteosarcoma cells
title_fullStr Enhanced Stim1 expression is associated with acquired chemo-resistance of cisplatin in osteosarcoma cells
title_full_unstemmed Enhanced Stim1 expression is associated with acquired chemo-resistance of cisplatin in osteosarcoma cells
title_short Enhanced Stim1 expression is associated with acquired chemo-resistance of cisplatin in osteosarcoma cells
title_sort enhanced stim1 expression is associated with acquired chemo-resistance of cisplatin in osteosarcoma cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486860/
https://www.ncbi.nlm.nih.gov/pubmed/28326487
http://dx.doi.org/10.1007/s13577-017-0167-9
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