title: Curcumin suppresses gastric tumor cell growth via ROS-mediated DNA polymerase γ depletion disrupting cellular bioenergetics.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Laboratory Animal Centre, Wenzhou Medical University, Wenzhou, Zhejiang, China.|State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health of the People's Republic of China, Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China.|School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Wang
authors.affiliation: Laboratory Animal Centre, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Xiwen
authors.initials: X
authors.lastname: Chen
authors.affiliation: School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Zhuanyun
authors.initials: Z
authors.lastname: Du
authors.affiliation: School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Gefei
authors.initials: G
authors.lastname: Li
authors.affiliation: Division of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Heart and Lung, Wenzhou, China.
authors.forename: Mayun
authors.initials: M
authors.lastname: Chen
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China. wzmcliangguang@163.com.|Wenzhou Medical University, University-Town, Wenzhou, Zhejiang, 325035, China. wzmcliangguang@163.com.
authors.forename: Guang
authors.initials: G
authors.lastname: Liang
authors.affiliation: Laboratory Animal Centre, Wenzhou Medical University, Wenzhou, Zhejiang, China. dry136@163.com.|Wenzhou Medical University, University-Town, Wenzhou, Zhejiang, 325035, China. dry136@163.com.
authors.forename: Tongke
authors.initials: T
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000008:administration & dosage* / Q000494:pharmacology; D000074002:DNA Polymerase gamma / Q000235:genetics* / Q000378:metabolism*; D004734:Energy Metabolism / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D000074002:DNA Polymerase gamma; C413027:POLG protein, human; D003474:Curcumin
keywords: Cellular bioenergetics; Curcumin; Gastric cancer; POLG; ROS