title: EGFR mediates LPA-induced proteolytic enzyme expression and ovarian cancer invasion: inhibition by resveratrol.
abstract: Lysophosphatidic acid (LPA) augments proliferation and metastasis of various cancer cells. We recently identified a critical role of the Rho/ROCK pathway for LPA-induced proteolytic enzyme expression and cancer cell progression. In the present study, we elucidate the underlying mechanisms by which LPA induces Rho activation and subsequent cellular invasion, and the reversal of these effects by resveratrol. We observed that both Gi and G13 contribute to LPA-induced EGFR activation. The activated EGFR in turn initiates a Ras/Rho/ROCK signaling cascade, leading to proteolytic enzyme secretion. Further we provide evidence that resveratrol inhibits EGFR phosphorylation and subsequent activation of a Ras/Rho/ROCK signaling. Therefore, we demonstrate a mechanistic cascade of LPA activating EGFR through Gi and G13 thus inducing a Ras/Rho/ROCK signaling for proteolytic enzyme expression and ovarian cancer cell invasion, as well as interference of the cascade by resveratrol through blocking EGFR phosphorylation.
authors.affiliation: Department of Pharmacology, College of Medicine, Konyang University, Daejeon 302-718, Korea.
authors.forename: Kang Jin
authors.initials: KJ
authors.lastname: Jeong
authors.forename: Kyung Hwa
authors.initials: KH
authors.lastname: Cho
authors.forename: Nattapon
authors.initials: N
authors.lastname: Panupinthu
authors.forename: Hoon
authors.initials: H
authors.lastname: Kim
authors.forename: Jaeku
authors.initials: J
authors.lastname: Kang
authors.forename: Chang Gyo
authors.initials: CG
authors.lastname: Park
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Hoi Young
authors.initials: HY
authors.lastname: Lee
mesh_terms: D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008246:Lysophospholipids / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D008246:Lysophospholipids; D013267:Stilbenes; C512478:EGFR protein, human; D066246:ErbB Receptors; C032881:lysophosphatidic acid; D000077185:Resveratrol