Epithelial-mesenchymal transition of ovarian cancer cells is sustained by Rac1 through simultaneous activation of MEK1/2 and Src signaling pathways.
Epithelial-mesenchymal transition (EMT) is regarded as a crucial contributing factor to cancer progression. Diverse factors have been identified as potent EMT inducers in ovarian cancer. However, molecular mechanism sustaining EMT of ovarian cancer cells remains elusive. Here we show that the presence of SOS1/EPS8/ABI1 complex is critical for sustained EMT traits of ovarian cancer cells. Consistent with the role of SOS1/EPS8/ABI1 complex as a Rac1-specific guanine nucleotide exchange factor, depleting Rac1 results in the loss of most of mesenchymal traits in mesenchymal-like ovarian cancer cells, whereas expressing constitutively active Rac1 leads to EMT in epithelial-like ovarian cancer cells. With the aid of clinically tested inhibitors targeting various EMT-associated signaling pathways, we show that only combined treatment of mitogen-activated extracellular signal-regulated kinase 1/2 (MEK1/2) and Src inhibitors can abolish constitutively active Rac1-led EMT and mesenchymal traits displayed by mesenchymal-like ovarian cancer cells. Further experiments also reveal that EMT can be induced in epithelial-like ovarian cancer cells by co-expressing constitutively active MEK1 and Src rather than either alone. As the activities of Erk and Src are higher in ovarian cancer cells with constitutively active Rac1, we conclude that Rac1 sustains ovarian cancer cell EMT through simultaneous activation of MEK1/2 and Src signaling pathways. Importantly, we demonstrate that combined use of MEK1/2 and Src inhibitors effectively suppresses development of intraperitoneal xenografts and prolongs the survival of ovarian cancer-bearing mice. This study suggests that cocktail of MEK1/2 and Src inhibitors represents an effective therapeutic strategy against ovarian cancer progression.
Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai, China.|E-institute of Shanghai Municipal Education Committee, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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D
Fang
Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, China.
H
H
Chen
Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL, USA.
J Y
JY
Zhu
Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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W
Wang
Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA, USA.|Georgia Cancer Center, Augusta University, Augusta, GA, USA.
Y
Y
Teng
Georgia Cancer Center, Augusta University, Augusta, GA, USA.
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HF
Ding
Department of Cardiology, Changhai Hospital, Shanghai, China.
Q
Q
Jing
Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai, China.|E-institute of Shanghai Municipal Education Committee, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
S-B
SB
Su
Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai, China.|E-institute of Shanghai Municipal Education Committee, Shanghai University of Traditional Chinese Medicine, Shanghai, China.|Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL, USA.
S
S
Huang
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000378:metabolism*; D048370:MAP Kinase Kinase 2 / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012097:Repressor Proteins / Q000378:metabolism; D020837:SOS1 Protein / Q000378:metabolism; D015398:Signal Transduction; D000071416:Twist Transcription Factors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism*
C513733:ABI1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C489989:EPS8 protein, human; D018398:Homeodomain Proteins; D047428:Protein Kinase Inhibitors; D012097:Repressor Proteins; D020837:SOS1 Protein; D000071416:Twist Transcription Factors; C486307:ZEB1 protein, human; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1; D019061:src-Family Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D020830:rac1 GTP-Binding Protein