Investigation of energy metabolism in human gastrointestinal cancer cells regulating tumor growth and the sensitivity to biguanide drugs
博士 === 國立陽明大學 === 藥理學研究所 === 103 === 英文摘要 Gastrointestinal (GI) cancers are gastrointestinal tract and accessory organs-related cancers including gastric and liver cancers. Dysregulation of cellular energetics was recently included as one of the cancer hallmarks. Several...
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ndltd-TW-103YM0055500142016-08-17T04:23:23Z http://ndltd.ncl.edu.tw/handle/30469335729566003995 Investigation of energy metabolism in human gastrointestinal cancer cells regulating tumor growth and the sensitivity to biguanide drugs 人類消化系統癌細胞之能量代謝調控腫瘤生長及對雙胍類藥物感受性之研究 Chia-Chi Hsu 許家齊 博士 國立陽明大學 藥理學研究所 103 英文摘要 Gastrointestinal (GI) cancers are gastrointestinal tract and accessory organs-related cancers including gastric and liver cancers. Dysregulation of cellular energetics was recently included as one of the cancer hallmarks. Several proteins have been identified in the regulation of cancer metabolism including SIRT3. SIRT3 is a protein located in mitochondrial matrix and regulates various cellular functions including fatty acid synthesis, mitochondrial respiration and redox homeostasis. Previous studies showed that SIRT3 serves as a tumor suppressor in many types of cancer. However, the role of SIRT3 in gastric cancer is still controversial. Biguanide drugs which inhibit mitochondrial Complex I and repress mTOR signaling are clinically used to treat type 2 diabetes mellitus (T2DM) patients and were recently found to reduce the risk of hepatocellular carcinoma (HCC) in T2DM patients. However, whether alteration of energy metabolism is involved in regulating the sensitivity of HCC to biguanide drugs is unclear. In part 1 of the present study, the SIRT3 mRNA expression in gastric cancer (GC) was found to be positively correlated with patient’s overall survival by analyzing the cancer biomedical informatics grid (caBIG) and gene expression omnibus (GEO) database. However, the analytic result from the cancer genome atlas (TCGA) database showed that neither overall survival nor clinical stage has a significant correlation with SIRT3 mRNA expression in gastric cancer tissue. Knock-down of SIRT3 in GC cell lines significantly decreased extracellular acidification rate (ECAR), glucose uptake rate and GLUT1 gene expression. It was found that knock-down of SIRT3 decreased the in vitro growth rate of gastric cancer cells SC-M1, but increased the tumor growth rate in vivo. In part 2 of the present study, four HCC cell lines were treated with mitochondrial inhibitors (rotenone and oligomycin) and biguanide drugs (phenformin and metformin). The results showed that the HCC cells, which had a higher mitochondrial respiration rate, were more sensitive to these treatments; whereas the HCC cells which exhibited higher rate of glycolysis were more resistant. Replacing glucose with galactose in cultural medium was used to alter energy metabolism from glycolysis to mitochondrial respiration, and then the sensitivity of HCC cells to mitochondrial inhibitors and biguanide drugs was increased after altering energy metabolism. Moreover, this study revealed that mitochondrial inhibitors reduced hypoxia-inducible factor-1α (HIF-1α) protein synthesis through AMPK-dependent manner in HepG2 cells. The energy metabolism change enhanced AMP-activated protein kinase (AMPK) activation, mTOR repression and downregulation of cyclin D1 and Mcl-1 in response to the mitochondrial inhibitors and biguanide drugs. In conclusion, these results from part 1 study suggest that SIRT3 exhibits different effects on cell growth rate between in vitro and in vivo, indicating that tumor microenvironment might play an important role in the regulation of SIRT3-mediated gastric cancer cell growth. Further investigation is necessary for understanding the role of SIRT3 in the communication between GC cells and tumor-associated cells, which might provide a strategy for GC therapy. The results from part 2 study suggest that elevating mitochondrial oxidative metabolism may upregulate the sensitivity of HCC cells to biguanide drugs. Therefore, enhancing the mitochondrial oxidative metabolism in combination with biguanide drugs may be a useful therapeutic strategy for HCC. Hsin-Chen Lee 李新城 2015 學位論文 ; thesis 133 zh-TW |
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博士 === 國立陽明大學 === 藥理學研究所 === 103 === 英文摘要
Gastrointestinal (GI) cancers are gastrointestinal tract and accessory organs-related cancers including gastric and liver cancers. Dysregulation of cellular energetics was recently included as one of the cancer hallmarks. Several proteins have been identified in the regulation of cancer metabolism including SIRT3. SIRT3 is a protein located in mitochondrial matrix and regulates various cellular functions including fatty acid synthesis, mitochondrial respiration and redox homeostasis. Previous studies showed that SIRT3
serves as a tumor suppressor in many types of cancer. However, the role of SIRT3 in gastric cancer is still controversial. Biguanide drugs which inhibit mitochondrial Complex I and repress mTOR signaling are clinically used to treat type 2 diabetes mellitus (T2DM) patients and were recently found to
reduce the risk of hepatocellular carcinoma (HCC) in T2DM patients. However, whether alteration of energy metabolism is involved in regulating the sensitivity of HCC to biguanide drugs is unclear. In part 1 of the present study, the SIRT3 mRNA expression in gastric cancer (GC) was found to be positively correlated with patient’s overall survival by analyzing the cancer biomedical informatics grid (caBIG) and gene expression omnibus (GEO) database. However, the analytic result from the cancer genome atlas (TCGA) database showed that neither overall survival nor clinical stage has a significant correlation with SIRT3 mRNA expression in gastric cancer tissue. Knock-down of SIRT3 in GC cell lines significantly decreased extracellular acidification rate (ECAR), glucose uptake rate and GLUT1 gene expression. It was found that knock-down of SIRT3 decreased the in vitro growth rate of gastric cancer cells
SC-M1, but increased the tumor growth rate in vivo. In part 2 of the present study, four HCC cell lines were treated with mitochondrial inhibitors (rotenone and oligomycin) and biguanide drugs (phenformin and metformin). The results showed that the HCC cells, which had a higher mitochondrial respiration rate, were more sensitive to these treatments; whereas the HCC cells which exhibited higher rate of glycolysis were more resistant. Replacing glucose with galactose in cultural medium was used to alter energy metabolism from
glycolysis to mitochondrial respiration, and then the sensitivity of HCC cells to mitochondrial inhibitors and biguanide drugs was increased after altering
energy metabolism. Moreover, this study revealed that mitochondrial inhibitors reduced hypoxia-inducible factor-1α (HIF-1α) protein synthesis through
AMPK-dependent manner in HepG2 cells. The energy metabolism change enhanced AMP-activated protein kinase (AMPK) activation, mTOR repression and downregulation of cyclin D1 and Mcl-1 in response to the mitochondrial inhibitors and biguanide drugs. In conclusion, these results from part 1 study suggest that SIRT3 exhibits different effects on cell growth rate between in
vitro and in vivo, indicating that tumor microenvironment might play an important role in the regulation of SIRT3-mediated gastric cancer cell growth.
Further investigation is necessary for understanding the role of SIRT3 in the communication between GC cells and tumor-associated cells, which might provide a strategy for GC therapy. The results from part 2 study suggest that elevating mitochondrial oxidative metabolism may upregulate the sensitivity of HCC cells to biguanide drugs. Therefore, enhancing the mitochondrial oxidative metabolism in combination with biguanide drugs may be a useful therapeutic strategy for HCC.
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author2 |
Hsin-Chen Lee |
author_facet |
Hsin-Chen Lee Chia-Chi Hsu 許家齊 |
author |
Chia-Chi Hsu 許家齊 |
spellingShingle |
Chia-Chi Hsu 許家齊 Investigation of energy metabolism in human gastrointestinal cancer cells regulating tumor growth and the sensitivity to biguanide drugs |
author_sort |
Chia-Chi Hsu |
title |
Investigation of energy metabolism in human gastrointestinal cancer cells regulating tumor growth and the sensitivity to biguanide drugs |
title_short |
Investigation of energy metabolism in human gastrointestinal cancer cells regulating tumor growth and the sensitivity to biguanide drugs |
title_full |
Investigation of energy metabolism in human gastrointestinal cancer cells regulating tumor growth and the sensitivity to biguanide drugs |
title_fullStr |
Investigation of energy metabolism in human gastrointestinal cancer cells regulating tumor growth and the sensitivity to biguanide drugs |
title_full_unstemmed |
Investigation of energy metabolism in human gastrointestinal cancer cells regulating tumor growth and the sensitivity to biguanide drugs |
title_sort |
investigation of energy metabolism in human gastrointestinal cancer cells regulating tumor growth and the sensitivity to biguanide drugs |
publishDate |
2015 |
url |
http://ndltd.ncl.edu.tw/handle/30469335729566003995 |
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