title: Gelsolin-Cu/ZnSOD interaction alters intracellular reactive oxygen species levels to promote cancer cell invasion.
abstract: The actin-binding protein, gelsolin, is a well known regulator of cancer cell invasion. However, the mechanisms by which gelsolin promotes invasion are not well established. As reactive oxygen species (ROS) have been shown to promote cancer cell invasion, we investigated on the hypothesis that gelsolin-induced changes in ROS levels may mediate the invasive capacity of colon cancer cells.Herein, we show that increased gelsolin enhances the invasive capacity of colon cancer cells, and this is mediated via gelsolin's effects in elevating intracellular superoxide (O2.-) levels. We also provide evidence for a novel physical interaction between gelsolin and Cu/ZnSOD, that inhibits the enzymatic activity of Cu/ZnSOD, thereby resulting in a sustained elevation of intracellular O2.-. Using microarray data of human colorectal cancer tissues from Gene Omnibus, we found that gelsolin gene expression positively correlates with urokinase plasminogen activator (uPA), an important matrix-degrading protease invovled in cancer invasion. Consistent with the in vivo evidence, we show that increased levels of O2.- induced by gelsolin overexpression triggers the secretion of uPA. We further observed reduction in invasion and intracellular O2.- levels in colon cancer cells, as a consequence of gelsolin knockdown using two different siRNAs. In these cells, concurrent repression of Cu/ZnSOD restored intracellular O2.- levels and rescued invasive capacity.Our study therefore identified gelsolin as a novel regulator of intracellular O2.- in cancer cells via interacting with Cu/ZnSOD and inhibiting its enzymatic activity. Taken together, these findings provide insight into a novel function of gelsolin in promoting tumor invasion by directly impacting the cellular redox milieu.
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Lalchhandami
authors.initials: L
authors.lastname: Tochhawng
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Shuo
authors.initials: S
authors.lastname: Deng
authors.affiliation: Bioinformatics Group, Bioscience Core Laboratory, King Abdullah University of Science and Technology (KAUST), Kingdom of Saudi Arabia.
authors.forename: Ganesan
authors.initials: G
authors.lastname: Pugalenthi
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Cancer Science Institute of Singapore, National University of Singapore, Singapore.|National University Cancer Institute, Singapore.|Curtin Health Innovation Research Institute, Biosciences Research Precinct, School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, WA, Australia.|Department of Biological Sciences, University of North Texas, Denton, TX, USA.
authors.forename: Alan Prem
authors.initials: AP
authors.lastname: Kumar
authors.affiliation: Department of Pathology, Singapore General Hospital, Singapore.
authors.forename: Kiat Hon
authors.initials: KH
authors.lastname: Lim
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Tuan Zea
authors.initials: TZ
authors.lastname: Tan
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Henry
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Shing Chuan
authors.initials: SC
authors.lastname: Hooi
authors.affiliation: Department of General Surgery, Singapore General Hospital, Singapore.|Department of General Surgery, Mount Elizabeth Hospital, Singapore.
authors.forename: Yaw Chong
authors.initials: YC
authors.lastname: Goh
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, United Kingdom.
authors.forename: Sutherland K
authors.initials: SK
authors.lastname: Maciver
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, Perth, Western Australia.|NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore.|Singapore-MIT Alliance, Singapore.
authors.forename: Shazib
authors.initials: S
authors.lastname: Pervaiz
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|National University Cancer Institute, Singapore.
authors.forename: Celestial T
authors.initials: CT
authors.lastname: Yap
mesh_terms: D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018260:Gelsolin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D008958:Models, Molecular; D009361:Neoplasm Invasiveness; D011485:Protein Binding; D000072417:Protein Domains; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000072105:Superoxide Dismutase-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*
chemical_list: D018260:Gelsolin; D017382:Reactive Oxygen Species; D000072105:Superoxide Dismutase-1; D014568:Urokinase-Type Plasminogen Activator
keywords: Cu/ZnSOD; ROS; antioxidant; cytoskeleton; gelsolin; invasion; Autophagy