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Synthetic 8‐hydroxygdeoxyguanosine paradoxically inhibited metastasis of pancreatic cancer through concerted inhibitions of ERM and Rho‐GTPase
Author(s) -
Han YoungMin,
Park JongMin,
Chung Myung Hee,
Kwon Chang Il,
Ko Kwang Hyun,
Hahm Ki Baik
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.824.10
Subject(s) - cell migration , cancer research , chemistry , metastasis , rho kinase inhibitor , matrix metalloproteinase , rac1 , epithelial–mesenchymal transition , microbiology and biotechnology , focal adhesion , cancer cell , cell , rho associated protein kinase , cancer , signal transduction , medicine , biology , biochemistry
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 8‐OHdG 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.