Low glucose and metformin-induced apoptosis of human ovarian cancer cells is connected to ASK1 via mitochondrial and endoplasmic reticulum stress-associated pathways
Abstract Background Metformin, a first-line drug for type 2 diabetes, could induce apoptosis in cancer cells. However, the concentration of glucose affects the effect of metformin, especially low glucose in the culture medium can enhance the cytotoxicity of metformin on cancer cells. Since mitochond...
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doaj-af916e5a3b80409ca2475064aaaf2afe2020-11-25T02:22:48ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662019-02-0138111410.1186/s13046-019-1090-6Low glucose and metformin-induced apoptosis of human ovarian cancer cells is connected to ASK1 via mitochondrial and endoplasmic reticulum stress-associated pathwaysLiwei Ma0Jianwei Wei1Junhu Wan2Weiwei Wang3Li Wang4Yongjie Yuan5Zijun Yang6Xianzhi Liu7Liang Ming8Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Neurosurgery, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Pathology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Pathology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Interventional Neurology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Nephropathy, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Neurosurgery, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou UniversityAbstract Background Metformin, a first-line drug for type 2 diabetes, could induce apoptosis in cancer cells. However, the concentration of glucose affects the effect of metformin, especially low glucose in the culture medium can enhance the cytotoxicity of metformin on cancer cells. Since mitochondria and endoplasmic reticulum is vital for maintaining cell homeostasis, we speculate that low glucose and metformin-induced cell apoptosis may be associated with mitochondria and endoplasmic reticulum. ASK1, as apoptosis signaling regulating kinase 1, is associated with cell apoptosis and mitochondrial damage. This study was designed to investigate the functional significance of ASK1, mitochondria and endoplasmic reticulum and underlying mechanism in low glucose and metformin-induced cell apoptosis. Methods An MTT assay was used to evaluate cell viability in SKOV3, OVCAR3 and HO8910 human ovarian cancer cells. Cell apoptosis was analyzed by flow cytometry. The expression of ASK1 was inhibited using a specific pharmacological inhibitor or ASK1-siRNA. Immunofluorescence was used to detect mitochondrial damage and ER stress. Nude mouse xenograft models were given metformin or/and NQDI-1, and ASK1 expression was detected using immunoblotting. In addition, subcellular fractionation of mitochondria was performed to assay the internal connection between ASK1 and mitochondria. Results The present study found that low glucose in culture medium enhanced the anticancer effect of metformin in human ovarian cancer cells. Utilization of a specific pharmacological inhibitor or ASK1-siRNA identified a potential role for ASK1 as an apoptotic protein in the regulation of low glucose and metformin-induced cell apoptosis via ASK1-mediated mitochondrial damage through the ASK1/Noxa pathway and via ER stress through the ROS/ASK1/JNK pathway. Moreover, ASK1 inhibition weakened the antitumor activity of metformin in vivo. Thus, mitochondrial damage and ER stress play a crucial role in low glucose–enhanced metformin cytotoxicity in human ovarian cancer cells. Conclusions These data suggested that low glucose and metformin induce cell apoptosis via ASK1-mediated mitochondrial damage and ER stress. These findings indicated that the effect of metformin in anticancer treatment may be related to cell culture conditions.http://link.springer.com/article/10.1186/s13046-019-1090-6Mitochondrial damageER stressASK1MetforminOvarian cancer |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Liwei Ma Jianwei Wei Junhu Wan Weiwei Wang Li Wang Yongjie Yuan Zijun Yang Xianzhi Liu Liang Ming |
spellingShingle |
Liwei Ma Jianwei Wei Junhu Wan Weiwei Wang Li Wang Yongjie Yuan Zijun Yang Xianzhi Liu Liang Ming Low glucose and metformin-induced apoptosis of human ovarian cancer cells is connected to ASK1 via mitochondrial and endoplasmic reticulum stress-associated pathways Journal of Experimental & Clinical Cancer Research Mitochondrial damage ER stress ASK1 Metformin Ovarian cancer |
author_facet |
Liwei Ma Jianwei Wei Junhu Wan Weiwei Wang Li Wang Yongjie Yuan Zijun Yang Xianzhi Liu Liang Ming |
author_sort |
Liwei Ma |
title |
Low glucose and metformin-induced apoptosis of human ovarian cancer cells is connected to ASK1 via mitochondrial and endoplasmic reticulum stress-associated pathways |
title_short |
Low glucose and metformin-induced apoptosis of human ovarian cancer cells is connected to ASK1 via mitochondrial and endoplasmic reticulum stress-associated pathways |
title_full |
Low glucose and metformin-induced apoptosis of human ovarian cancer cells is connected to ASK1 via mitochondrial and endoplasmic reticulum stress-associated pathways |
title_fullStr |
Low glucose and metformin-induced apoptosis of human ovarian cancer cells is connected to ASK1 via mitochondrial and endoplasmic reticulum stress-associated pathways |
title_full_unstemmed |
Low glucose and metformin-induced apoptosis of human ovarian cancer cells is connected to ASK1 via mitochondrial and endoplasmic reticulum stress-associated pathways |
title_sort |
low glucose and metformin-induced apoptosis of human ovarian cancer cells is connected to ask1 via mitochondrial and endoplasmic reticulum stress-associated pathways |
publisher |
BMC |
series |
Journal of Experimental & Clinical Cancer Research |
issn |
1756-9966 |
publishDate |
2019-02-01 |
description |
Abstract Background Metformin, a first-line drug for type 2 diabetes, could induce apoptosis in cancer cells. However, the concentration of glucose affects the effect of metformin, especially low glucose in the culture medium can enhance the cytotoxicity of metformin on cancer cells. Since mitochondria and endoplasmic reticulum is vital for maintaining cell homeostasis, we speculate that low glucose and metformin-induced cell apoptosis may be associated with mitochondria and endoplasmic reticulum. ASK1, as apoptosis signaling regulating kinase 1, is associated with cell apoptosis and mitochondrial damage. This study was designed to investigate the functional significance of ASK1, mitochondria and endoplasmic reticulum and underlying mechanism in low glucose and metformin-induced cell apoptosis. Methods An MTT assay was used to evaluate cell viability in SKOV3, OVCAR3 and HO8910 human ovarian cancer cells. Cell apoptosis was analyzed by flow cytometry. The expression of ASK1 was inhibited using a specific pharmacological inhibitor or ASK1-siRNA. Immunofluorescence was used to detect mitochondrial damage and ER stress. Nude mouse xenograft models were given metformin or/and NQDI-1, and ASK1 expression was detected using immunoblotting. In addition, subcellular fractionation of mitochondria was performed to assay the internal connection between ASK1 and mitochondria. Results The present study found that low glucose in culture medium enhanced the anticancer effect of metformin in human ovarian cancer cells. Utilization of a specific pharmacological inhibitor or ASK1-siRNA identified a potential role for ASK1 as an apoptotic protein in the regulation of low glucose and metformin-induced cell apoptosis via ASK1-mediated mitochondrial damage through the ASK1/Noxa pathway and via ER stress through the ROS/ASK1/JNK pathway. Moreover, ASK1 inhibition weakened the antitumor activity of metformin in vivo. Thus, mitochondrial damage and ER stress play a crucial role in low glucose–enhanced metformin cytotoxicity in human ovarian cancer cells. Conclusions These data suggested that low glucose and metformin induce cell apoptosis via ASK1-mediated mitochondrial damage and ER stress. These findings indicated that the effect of metformin in anticancer treatment may be related to cell culture conditions. |
topic |
Mitochondrial damage ER stress ASK1 Metformin Ovarian cancer |
url |
http://link.springer.com/article/10.1186/s13046-019-1090-6 |
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