Synthetic 8-hydroxydeoxyguanosine inhibited metastasis of pancreatic cancer through concerted inhibitions of ERM and Rho-GTPase
- Authors
- Park, Jong-Min; Han, Young-Min; Jeong, Migyeong; Chung, Myung Hee; Kwon, Chang Il; Ko, Kwang Hyun; Hahm, Ki Baik
- Issue Date
- Sep-2017
- Publisher
- ELSEVIER SCIENCE INC
- Keywords
- 8-hydroxydeoxyguanosine; ERM; EMT; Metastasis; Pancreatic cancer
- Citation
- FREE RADICAL BIOLOGY AND MEDICINE, v.110, pp.151 - 161
- Journal Title
- FREE RADICAL BIOLOGY AND MEDICINE
- Volume
- 110
- Start Page
- 151
- End Page
- 161
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/5724
- DOI
- 10.1016/j.freeradbiomed.2017.06.003
- ISSN
- 0891-5849
- Abstract
- 8-hydroxydeoxyguanosine (8-OHdG) is generated consequent to oxidative stress, but its paradoxical anti-oxidative, anti-inflammatory, and anti-mutagenic effects via Rho-GTPase inhibition were noted in various models of inflammation and cancer. Metastasis occurs through cell detachment, epithelial-mesenchymal transition (EMT), and cell migration; during these processes, changes in cell morphology are initiated through Rho-GTPase-dependent actin cytoskeleton polymerization. In this study, we explored the anti-metastatic mechanisms of 8OHdG in Panc-1 pancreatic cancer cells. 8-OHdG inhibits cell migration by inactivating ERM and Rho-GTPase proteins, and inhibiting focal adhesion kinase (FAK) and matrix metalloproteinases (MMPs). At 15 min, 8-OHdG significantly inactivated ERM (p<0.05) and led to a significant retardation of wound healing; siERM and H1152 (ROCK inhibitor) had similar effects (p<0.05). However, FAK inhibitor 14, DPI (NOX inhibitor), and NAC (antioxidant) significantly delayed wound healing without inhibiting ERM or CD44 (p<0.05). In the experiments on cell migration, siERM, siCD44, DPI, and 8-OHdG significantly inhibited MMPs. 8-OHdG significantly decreased DCF-DA activation in Panc-1 pancreatic cancer cells and down-regulated NOXs (nox-1, nox-2, and nox-3). Finally, all of these anti-migration actions of 8-OHdG resulted in significant inhibition of EMT, as evidenced by the up-regulation of ZO-1 and claudin-1 and down-regulation of vimentin. We found significant inhibition of lung metastasis of Panc-1 cells by 8-OHdG. In conclusion, exogenous 8-OHdG had potent anti-metastasis effects mediated by either ERM or Rho GTPase inhibition in metastasis-prone pancreatic cancer cells.
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