AMPK在EMT扮演角色之探討

Abstract

AMPK為serine/threonine蛋白激酶，在真核細胞可感受能量之變化，調控能量之平衡。EMT (epithelial-mesenchymal transition)為癌細胞具備侵襲和轉移能力之重要過程，E-cadherin喪失是EMT之關鍵指標；E-cadherin的再表現可引發EMT之相反過程MET (mesenchymal-epithelial transition)。在肺腺癌上皮細胞，TGF-β可引發EMT。本實驗發現在肺腺癌上皮細胞，AMPK活化劑AICAR和2-DG皆可降低E-cadherin之表現，而AMPK抑制劑Ara-A和Compound C則可回復TGF-β所降低之E-cadherin；AMPK si-RNA亦可增加E-cadherin之表現，並抑制TGF-β引發之EMT，E-cadherin mRNA表現亦增加，表示AMPK會調控E-cadherin之基因轉錄。Snail和Slug為E-cadheirn 之repressor，進一步的研究發現，抑制AMPK可降低Snail和Slug之蛋白表現，但不影響其mRNA之表現，因此AMPK可能會抑制E-cadherin之基因轉錄，抑制AMPK或許是防止癌症轉移之治療策略。

AMPK is a serine/threonine protein kinase that serves as an energy sensor in all eukaryoic cells, regulating energy balance. Epithelial-Mesenchymal Transition (EMT) is a crucial process for cancer cells to acquire invasive and metastatic phenotype. Loss of E-cadherin is a hallmark of EMT. Thus, re-expression of E-cadherin could elicit inverse process Mesenchymal-Epithelial Transition (MET). In lung adenocarcinomas, TGF-β is a major inducer of EMT. In this study, we found that AMPK activators AICAR and 2-DG downregulated E-cadherin expression, while AMPK inhibitors Ara-A and Compound C reversed E-cadherin expression which was downregulated by TGF-β in lung adenocarcinomas. Importantly, RNA ineference-mediated knockdown of AMPK suppressed TGF-β induced EMT through upregulation of E-cadherin expression. Silencing of AMPK also upregulated E-cadherin mRNA expression, suggesting that AMPK could regulate E-cadherin gene transcription. Snail and Slug were E-cadherin transcriptional repressors. Silencing of AMPK downregulated the protein but not mRNA expression of Snail and Slug, indicating that AMPK might inhibit E-cadherin gene expression. Targeting AMPK may be a useful strategy to retard cancer cell invasion and metastasis.