Gelsolin-Cu/ZnSOD interaction alters intracellular reactive oxygen species levels to promote cancer cell invasion
Type
ArticleAuthors
Tochhawng, LalchhandamiDeng, 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.
KAUST Department
BioinformaticsBioscience Core Lab
Date
2016-07-06Online Publication Date
2016-07-06Print Publication Date
2016-08-16Permanent link to this record
http://hdl.handle.net/10754/622049
Metadata
Show full item recordAbstract
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.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.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.Publisher
Impact Journals, LLCJournal
OncotargetPubMed ID
27391159Additional Links
http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=10451ae974a485f413a2113503eed53cd6c53
10.18632/oncotarget.10451
Scopus Count
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