Curcumin suppresses gastric tumor cell growth via ROS-mediated DNA polymerase γ depletion disrupting cellular bioenergetics
Abstract Background Curcumin, as a pro-apoptotic agent, is extensively studied to inhibit tumor cell growth of various tumor types. Previous work has demonstrated that curcumin inhibits cancer cell growth by targeting multiple signaling transduction and cellular processes. However, the role of curcu...
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doaj-a169f7d650664e43893705986525e6962020-11-25T00:16:51ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662017-03-0136111410.1186/s13046-017-0513-5Curcumin suppresses gastric tumor cell growth via ROS-mediated DNA polymerase γ depletion disrupting cellular bioenergeticsLihua Wang0Xiwen Chen1Zhuanyun Du2Gefei Li3Mayun Chen4Xi Chen5Guang Liang6Tongke Chen7Laboratory Animal Centre, Wenzhou Medical UniversityLaboratory Animal Centre, Wenzhou Medical UniversitySchool of Life Sciences, Wenzhou Medical UniversitySchool of Life Sciences, Wenzhou Medical UniversityDivision of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Heart and LungChemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical UniversityChemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical UniversityLaboratory Animal Centre, Wenzhou Medical UniversityAbstract Background Curcumin, as a pro-apoptotic agent, is extensively studied to inhibit tumor cell growth of various tumor types. Previous work has demonstrated that curcumin inhibits cancer cell growth by targeting multiple signaling transduction and cellular processes. However, the role of curcumin in regulating cellular bioenergetic processes remains largely unknown. Methods Western blotting and qRT-PCR were performed to analyze the protein and mRNA level of indicated molecules, respectively. RTCA, CCK-8 assay, nude mice xenograft assay, and in vivo bioluminescence imaging were used to visualize the effects of curcmin on gastric cancer cell growth in vitro and in vivo. Seahorse bioenergetics analyzer was used to investigate the alteration of oxygen consumption and aerobic glycolysis rate. Results Curcumin significantly inhibited gastric tumor cell growth, proliferation and colony formation. We further investigated the role of curcumin in regulating cellular redox homeostasis and demonstrated that curcumin initiated severe cellular apoptosis via disrupting mitochondrial homeostasis, thereby enhancing cellular oxidative stress in gastric cancer cells. Furthermore, curcumin dramatically decreased mtDNA content and DNA polymerase γ (POLG) which contributed to reduced mitochondrial oxygen consumption and aerobic glycolysis. We found that curcumin induced POLG depletion via ROS generation, and POLG knockdown also reduced oxidative phosphorylation (OXPHOS) activity and cellular glycolytic rate which was partially rescued by ROS scavenger NAC, indiating POLG plays an important role in the treatment of gastric cancer. Data in the nude mice model verified that curcumin treatment significantly attenuated tumor growth in vivo. Finally, POLG was up-regulated in human gastric cancer tissues and primary gastric cancer cell growth was notably suppressed due to POLG deficiency. Conclusions Together, our data suggest a novel mechanism by which curcumin inhibited gastric tumor growth through excessive ROS generation, resulting in depletion of POLG and mtDNA, and the subsequent disruption of cellular bioenergetics.http://link.springer.com/article/10.1186/s13046-017-0513-5CurcuminGastric cancerCellular bioenergeticsROSPOLG |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Lihua Wang Xiwen Chen Zhuanyun Du Gefei Li Mayun Chen Xi Chen Guang Liang Tongke Chen |
spellingShingle |
Lihua Wang Xiwen Chen Zhuanyun Du Gefei Li Mayun Chen Xi Chen Guang Liang Tongke Chen Curcumin suppresses gastric tumor cell growth via ROS-mediated DNA polymerase γ depletion disrupting cellular bioenergetics Journal of Experimental & Clinical Cancer Research Curcumin Gastric cancer Cellular bioenergetics ROS POLG |
author_facet |
Lihua Wang Xiwen Chen Zhuanyun Du Gefei Li Mayun Chen Xi Chen Guang Liang Tongke Chen |
author_sort |
Lihua Wang |
title |
Curcumin suppresses gastric tumor cell growth via ROS-mediated DNA polymerase γ depletion disrupting cellular bioenergetics |
title_short |
Curcumin suppresses gastric tumor cell growth via ROS-mediated DNA polymerase γ depletion disrupting cellular bioenergetics |
title_full |
Curcumin suppresses gastric tumor cell growth via ROS-mediated DNA polymerase γ depletion disrupting cellular bioenergetics |
title_fullStr |
Curcumin suppresses gastric tumor cell growth via ROS-mediated DNA polymerase γ depletion disrupting cellular bioenergetics |
title_full_unstemmed |
Curcumin suppresses gastric tumor cell growth via ROS-mediated DNA polymerase γ depletion disrupting cellular bioenergetics |
title_sort |
curcumin suppresses gastric tumor cell growth via ros-mediated dna polymerase γ depletion disrupting cellular bioenergetics |
publisher |
BMC |
series |
Journal of Experimental & Clinical Cancer Research |
issn |
1756-9966 |
publishDate |
2017-03-01 |
description |
Abstract Background Curcumin, as a pro-apoptotic agent, is extensively studied to inhibit tumor cell growth of various tumor types. Previous work has demonstrated that curcumin inhibits cancer cell growth by targeting multiple signaling transduction and cellular processes. However, the role of curcumin in regulating cellular bioenergetic processes remains largely unknown. Methods Western blotting and qRT-PCR were performed to analyze the protein and mRNA level of indicated molecules, respectively. RTCA, CCK-8 assay, nude mice xenograft assay, and in vivo bioluminescence imaging were used to visualize the effects of curcmin on gastric cancer cell growth in vitro and in vivo. Seahorse bioenergetics analyzer was used to investigate the alteration of oxygen consumption and aerobic glycolysis rate. Results Curcumin significantly inhibited gastric tumor cell growth, proliferation and colony formation. We further investigated the role of curcumin in regulating cellular redox homeostasis and demonstrated that curcumin initiated severe cellular apoptosis via disrupting mitochondrial homeostasis, thereby enhancing cellular oxidative stress in gastric cancer cells. Furthermore, curcumin dramatically decreased mtDNA content and DNA polymerase γ (POLG) which contributed to reduced mitochondrial oxygen consumption and aerobic glycolysis. We found that curcumin induced POLG depletion via ROS generation, and POLG knockdown also reduced oxidative phosphorylation (OXPHOS) activity and cellular glycolytic rate which was partially rescued by ROS scavenger NAC, indiating POLG plays an important role in the treatment of gastric cancer. Data in the nude mice model verified that curcumin treatment significantly attenuated tumor growth in vivo. Finally, POLG was up-regulated in human gastric cancer tissues and primary gastric cancer cell growth was notably suppressed due to POLG deficiency. Conclusions Together, our data suggest a novel mechanism by which curcumin inhibited gastric tumor growth through excessive ROS generation, resulting in depletion of POLG and mtDNA, and the subsequent disruption of cellular bioenergetics. |
topic |
Curcumin Gastric cancer Cellular bioenergetics ROS POLG |
url |
http://link.springer.com/article/10.1186/s13046-017-0513-5 |
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