Gelsolin-Cu/ZnSOD interaction alters intracellular reactive oxygen species levels to promote cancer cell invasion

Handle URI:
http://hdl.handle.net/10754/622049
Title:
Gelsolin-Cu/ZnSOD interaction alters intracellular reactive oxygen species levels to promote cancer cell invasion
Authors:
Tochhawng, Lalchhandami; Deng, Shuo; Ganesan, Pugalenthi; Kumar, Alan Prem; Lim, Kiat Hon; Yang, Henry; Hooi, Shing Chuan; Goh, Yaw Chong; Maciver, Sutherland K.; Pervaiz, Shazib; Yap, Celestial T.
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.
KAUST Department:
Biosciences Core Lab
Citation:
Tochhawng L, Deng S, Pugalenthi G, Kumar AP, Lim KH, et al. (2016) Gelsolin-Cu/ZnSOD interaction alters intracellular reactive oxygen species levels to promote cancer cell invasion. Oncotarget. Available: http://dx.doi.org/10.18632/oncotarget.10451.
Publisher:
Impact Journals, LLC
Journal:
Oncotarget
Issue Date:
7-Jul-2016
DOI:
10.18632/oncotarget.10451
Type:
Article
ISSN:
1949-2553
Sponsors:
The authors thank Dr. Thai Tran (National University of Singapore) and Ms Yongkang Qiao (National University of Singapore) for their help in calcium measurement.
Additional Links:
http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=10451
Appears in Collections:
Articles; Bioscience Core Lab

Full metadata record

DC FieldValue Language
dc.contributor.authorTochhawng, Lalchhandamien
dc.contributor.authorDeng, Shuoen
dc.contributor.authorGanesan, Pugalenthien
dc.contributor.authorKumar, Alan Premen
dc.contributor.authorLim, Kiat Honen
dc.contributor.authorYang, Henryen
dc.contributor.authorHooi, Shing Chuanen
dc.contributor.authorGoh, Yaw Chongen
dc.contributor.authorMaciver, Sutherland K.en
dc.contributor.authorPervaiz, Shaziben
dc.contributor.authorYap, Celestial T.en
dc.date.accessioned2016-12-21T13:50:18Z-
dc.date.available2016-12-21T13:50:18Z-
dc.date.issued2016-07-07en
dc.identifier.citationTochhawng L, Deng S, Pugalenthi G, Kumar AP, Lim KH, et al. (2016) Gelsolin-Cu/ZnSOD interaction alters intracellular reactive oxygen species levels to promote cancer cell invasion. Oncotarget. Available: http://dx.doi.org/10.18632/oncotarget.10451.en
dc.identifier.issn1949-2553en
dc.identifier.doi10.18632/oncotarget.10451en
dc.identifier.urihttp://hdl.handle.net/10754/622049-
dc.description.abstractThe 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.en
dc.description.sponsorshipThe authors thank Dr. Thai Tran (National University of Singapore) and Ms Yongkang Qiao (National University of Singapore) for their help in calcium measurement.en
dc.publisherImpact Journals, LLCen
dc.relation.urlhttp://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=10451en
dc.rightsAll site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.en
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/en
dc.subjectAntioxidanten
dc.subjectCu/ZnSODen
dc.subjectCytoskeletonen
dc.subjectGelsolinen
dc.subjectInvasionen
dc.subjectROSen
dc.titleGelsolin-Cu/ZnSOD interaction alters intracellular reactive oxygen species levels to promote cancer cell invasionen
dc.typeArticleen
dc.contributor.departmentBiosciences Core Laben
dc.identifier.journalOncotargeten
dc.eprint.versionPublisher's Version/PDFen
dc.contributor.institutionDepartment of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singaporeen
dc.contributor.institutionDepartment of Biotechnology, School of Life Sciences, Assam Don Bosco University, Azara, Guwahati, Indiaen
dc.contributor.institutionDepartment of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singaporeen
dc.contributor.institutionCancer Science Institute of Singapore, National University of Singapore, Singaporeen
dc.contributor.institutionNational University Cancer Institute, Singaporeen
dc.contributor.institutionCurtin Health Innovation Research Institute, Biosciences Research Precinct, School of Biomedical Sciences, Faculty of Health Sciences, Curtin UniversityWA, Australiaen
dc.contributor.institutionDepartment of Biological Sciences, University of North Texas, Denton, TX, United Statesen
dc.contributor.institutionDepartment of Pathology, Singapore General Hospital, Singaporeen
dc.contributor.institutionDepartment of General Surgery, Singapore General Hospital, Singaporeen
dc.contributor.institutionDepartment of General Surgery, Mount Elizabeth Hospital, Singaporeen
dc.contributor.institutionCentre for Integrative Physiology, University of Edinburgh, United Statesen
dc.contributor.institutionSchool of Biomedical Sciences, Faculty of Health Sciences, Curtin University, Perth, WA, Australiaen
dc.contributor.institutionNUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singaporeen
dc.contributor.institutionSingapore-MIT Alliance, Singaporeen
kaust.authorGanesan, Pugalenthien
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