title: Ghrelin induces colon cancer cell proliferation through the GHS-R, Ras, PI3K, Akt, and mTOR signaling pathways.
abstract: Colon cancer is the third most common malignancy worldwide. Recently, some interesting associations between ghrelin and cancer were reported, and it may participate in colon cancer development. In the present report, we explored the role of the growth hormone secretagogue receptor (GHS-R), Ras, phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR) pathways in the ghrelin-induced proliferation of human colon cancer cells. Ghrelin-caused HT-29 proliferation was reduced by [D-Lys3]-GHRP-6 (a GHS-R inhibitor). We also found that a dominant negative mutant of Ras (Ras DN), a PI3K inhibitor (LY 294002), an Akt DN, and an mTOR inhibitor (rapamycin) attenuated ghrelin-caused colon cancer cell proliferation. We found that ghrelin induced time-dependent increases in Ras activity. Moreover, ghrelin-mediated Akt Ser473 phosphorylation was attenuated by a Ras DN and LY 294002. Furthermore, a Ras DN, LY 294002, and an Akt DN all inhibited ghrelin-caused mTOR Ser2448 phosphorylation. These results indicate that the Ras/PI3K/Akt/mTOR cascade plays a critical role in ghrelin-induced colon cancer cell proliferation.
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Gi-Shih
authors.initials: GS
authors.lastname: Lien
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Chien-Huang
authors.initials: CH
authors.lastname: Lin
authors.affiliation: School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: You-Lan
authors.initials: YL
authors.lastname: Yang
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 110, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Ming-Shun
authors.initials: MS
authors.lastname: Wu
authors.affiliation: School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei 110, Taiwan. Electronic address: bcchen@tmu.edu.tw.
authors.forename: Bing-Chang
authors.initials: BC
authors.lastname: Chen
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology*; D054439:Ghrelin / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans; D009154:Mutation; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000378:metabolism*; D054440:Receptors, Ghrelin / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D054439:Ghrelin; D054440:Receptors, Ghrelin; D012694:Serine; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins
keywords: Colon cancer; Ghrelin; PI3K/Akt; Proliferation; Ras; mTOR