Oxidative stress enhances Axl-mediated cell migration through an Akt1/Rac1-dependent mechanism.
Persistent oxidative stress is common in cancer cells because of abnormal generation of reactive oxygen species (ROS) and has been associated with malignant phenotypes, such as chemotherapy resistance and metastasis. Both overexpression of Axl and abnormal ROS elevation have been linked to cell transformation and increased cell migration. However, the relationship between Axl and ROS in malignant cell migration has not been previously evaluated. Using an in vitro human lung cancer model, we examined the redox state of lung adenocarcinoma cell lines of low metastatic (CL1-0) and high metastatic (CL1-5) potentials. Here we report that Axl activation elicits ROS accumulation through the oxidase-coupled small GTPase Rac1. We also observed that oxidative stress could activate Axl phosphorylation to synergistically enhance cell migration. Further, Axl signaling activated by H2O2 treatment results in enhancement of cell migration via a PI3K/Akt-dependent pathway. The kinase activity of Axl is required for the Axl-mediated cell migration and prolongs the half-life of phospho-Akt under oxidative stress. Finally, downregulation of Akt1, but not Akt2, by RNAi in Axl-overexpressing cells inhibits the amount of activated Rac1 and the ability to migrate induced by H2O2 treatment. Together, these results show that a novel Axl-signaling cascade induced by H2O2 treatment triggers cell migration through the PI3K/Akt1/Rac1 pathway. Elucidation of redox regulation in Axl-related malignant migration may provide new molecular insights into the mechanisms underlying tumor progression.
National Institute of Cancer Research, National Health Research Institutes, Zhunan Town, Miaoli County 350, Taiwan, Republic of China; Center of Excellence for Cancer Research, Taipei Medical University, Taipei, Taiwan, Republic of China.
Jhy-Shrian
JS
Huang
National Institute of Cancer Research, National Health Research Institutes, Zhunan Town, Miaoli County 350, Taiwan, Republic of China.
Chun-Yu
CY
Cho
National Institute of Cancer Research, National Health Research Institutes, Zhunan Town, Miaoli County 350, Taiwan, Republic of China.
Chih-Chen
CC
Hong
National Institute of Cancer Research, National Health Research Institutes, Zhunan Town, Miaoli County 350, Taiwan, Republic of China.
Ming-De
MD
Yan
Center of Excellence for Cancer Research, Taipei Medical University, Taipei, Taiwan, Republic of China; Department of Surgery, Division of General Surgery, Taipei Medical University, Taipei, Taiwan, Republic of China.
Mao-Chih
MC
Hsieh
Division of Basic Medical Sciences, National Taichung Nursing College, Taichung, Taiwan, Republic of China.
Jong-Ding
JD
Lay
National Institute of Cancer Research, National Health Research Institutes, Zhunan Town, Miaoli County 350, Taiwan, Republic of China; Center of Excellence for Cancer Research, Taipei Medical University, Taipei, Taiwan, Republic of China; Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan, Republic of China.
Gi-Ming
GM
Lai
National Institute of Cancer Research, National Health Research Institutes, Zhunan Town, Miaoli County 350, Taiwan, Republic of China; Department of Internal Medicine and Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan, Republic of China.
Ann-Lii
AL
Cheng
National Institute of Cancer Research, National Health Research Institutes, Zhunan Town, Miaoli County 350, Taiwan, Republic of China. Electronic address: sechuang@nhri.org.tw.
Shuang-En
SE
Chuang
D000230:Adenocarcinoma / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D004789:Enzyme Activation; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008175:Lung Neoplasms / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000094963:Axl Receptor Tyrosine Kinase
D011518:Proto-Oncogene Proteins; C107953:RAC1 protein, human; D034741:RNA, Small Interfering; D006861:Hydrogen Peroxide; D019869:Phosphatidylinositol 3-Kinases; D020794:Receptor Protein-Tyrosine Kinases; C494918:AKT1 protein, human; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D020830:rac1 GTP-Binding Protein; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human
2′,7′-dichlorodihydrofluorescein diacetate; Akt1; Axl; DCF-DA; Free radicals; Gas6; NSCLC; Oxidative stress; ROS; RTK; Rac1; SOD; growth-arrest-specific 6; non-small-cell lung cancer; reactive oxygen species; receptor tyrosine kinase; superoxide dismutase