Research Papers: Autophagy and Cell Death:
Gelsolin-Cu/ZnSOD interaction alters intracellular reactive oxygen species levels to promote cancer cell invasion
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Abstract
Lalchhandami Tochhawng1, Shuo Deng1, Ganesan Pugalenthi3, Alan Prem Kumar2,4,5,6,7, Kiat Hon Lim8, Tuan Zea Tan4, Henry Yang4, Shing Chuan Hooi1, Yaw Chong Goh9,10, Sutherland K. Maciver11, Shazib Pervaiz1,12,13,14 and Celestial T. Yap1,5
1 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
2 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
3 Bioinformatics Group, Bioscience Core Laboratory, King Abdullah University of Science and Technology (KAUST), Kingdom of Saudi Arabia
4 Cancer Science Institute of Singapore, National University of Singapore, Singapore
5 National University Cancer Institute, Singapore
6 Curtin Health Innovation Research Institute, Biosciences Research Precinct, School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, WA, Australia
7 Department of Biological Sciences, University of North Texas, Denton, TX, USA
8 Department of Pathology, Singapore General Hospital, Singapore
9 Department of General Surgery, Singapore General Hospital, Singapore
10 Department of General Surgery, Mount Elizabeth Hospital, Singapore
11 Centre for Integrative Physiology, University of Edinburgh, United Kingdom
12 School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, Perth, Western Australia
13 NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore
14 Singapore-MIT Alliance, Singapore
Correspondence to:
Celestial T. Yap, email:
Shazib Pervaiz, email:
Keywords: invasion, gelsolin, cytoskeleton, Cu/ZnSOD, ROS, antioxidant
Received: December 21, 2015 Accepted: June 28, 2016 Published: July 06, 2016
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.
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