Ghrelin induces colon cancer cell proliferation through the GHS-R, Ras, PI3K, Akt, and mTOR signaling pathways

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• 作者：Gi-Shih Lien^a ; ¹ ; Chien-Huang Lin^b ; ¹ ; You-Lan Yang^c ; Ming-Shun Wu^a ; ^d ; Bing-Chang Chen^c ; ^{bcchen@tmu.edu.tw" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Colon cancer ; Ghrelin ; Proliferation ; Ras ; PI3K/Akt ; mTOR
• 刊名：European Journal of Pharmacology
• 出版年：2016
• 出版时间：5 April 2016
• 年：2016
• 卷：776
• 期：Complete
• 页码：124-131
• 全文大小：2126 K

文摘

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.