二甲双胍和葡萄糖饥饿会降低肝癌细胞的迁移能力：靶向AMPK激活以控制迁移。,Scientific Reports

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二甲双胍和葡萄糖饥饿会降低肝癌细胞的迁移能力：靶向AMPK激活以控制迁移。
Scientific Reports ( IF 3.8 ) Pub Date : 2019-02-26 , DOI: 10.1038/s41598-019-39556-w
Anabela C Ferretti ₁ , Florencia Hidalgo ₁ , Facundo M Tonucci ₁ , Evangelina Almada ₁ , Alejandro Pariani ₁ , María C Larocca ₁ , Cristián Favre ₁

Affiliation

肝细胞癌（HCC）是一种高度转移性癌症，预后很差。AMP激活激酶（AMPK）构成了抑制HCC进展的候选药物。首先，AMPK在HCC中被下调。其次，葡萄糖饥饿会通过AMPK诱导HCC细胞凋亡。相应地，二甲双胍激活AMPK并抑制HCC细胞增殖。然而，AMPK激活对HCC细胞侵袭性的影响仍然难以捉摸。在这里，在暴露于二甲双胍和葡萄糖饥饿的HCC细胞中研究了迁移/侵袭。分析了细胞活力，增殖和分化以及AMPK和PKA活化。此外，还评估了AMPKα激活环突变体的侵袭性。二甲双胍减少了细胞迁移，侵袭和上皮-间质转化，对AMPKα表达的干扰避免了二甲双胍的作用。葡萄糖剥夺增强了这些抗肿瘤作用。二甲双胍可同时激活AMPK，从而抑制PKA，而葡萄糖饥饿则增强了这两种作用。考虑到PKA可使AMPKα（S173）磷酸化降低AMPK活化，我们假设二甲双胍对PKA抑制作用的降低可以解释所观察到的抗肿瘤作用增加。支持这一点的是，在AMPK激活条件下，AMPKα（S173C）突变细胞的细胞迁移/侵袭进一步受到损害。二甲双胍是HCC细胞迁移/侵袭的强抑制剂，而葡萄糖限制增强了这种作用。葡萄糖饥饿增强了这两种作用。考虑到PKA可使AMPKα（S173）磷酸化降低AMPK活化，我们假设二甲双胍对PKA抑制作用的降低可以解释所观察到的抗肿瘤作用增加。支持这一点的是，在AMPK激活条件下，AMPKα（S173C）突变细胞的细胞迁移/侵袭进一步受到损害。二甲双胍是HCC细胞迁移/侵袭的强抑制剂，而葡萄糖限制增强了这种作用。葡萄糖饥饿增强了这两种作用。考虑到PKA可使AMPKα（S173）磷酸化降低AMPK活化，我们假设二甲双胍对PKA抑制作用的降低可以解释所观察到的抗肿瘤作用增加。支持这一点的是，在AMPK激活条件下，AMPKα（S173C）突变细胞的细胞迁移/侵袭进一步受到损害。二甲双胍是HCC细胞迁移/侵袭的强抑制剂，而葡萄糖限制增强了这种作用。

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Metformin and glucose starvation decrease the migratory ability of hepatocellular carcinoma cells: targeting AMPK activation to control migration.

Hepatocellular carcinoma (HCC) is a highly metastatic cancer with very poor prognosis. AMP activated kinase (AMPK) constitutes a candidate to inhibit HCC progression. First, AMPK is downregulated in HCC. Second, glucose starvation induces apoptosis in HCC cells via AMPK. Correspondingly, metformin activates AMPK and inhibits HCC cell proliferation. Nevertheless, the effect of AMPK activation on HCC cell invasiveness remains elusive. Here, migration/invasion was studied in HCC cells exposed to metformin and glucose starvation. Cell viability, proliferation and differentiation, as well as AMPK and PKA activation were analyzed. In addition, invasiveness in mutants of the AMPKα activation loop was assessed. Metformin decreased cell migration, invasion and epithelial-mesenchymal transition, and interference with AMPKα expression avoided metformin actions. Those antitumor effects were potentiated by glucose deprivation. Metformin activated AMPK at the same time that inhibited PKA, and both effects were enhanced by glucose starvation. Given that AMPKα(S173) phosphorylation by PKA decreases AMPK activation, we hypothesized that the reduction of PKA inhibitory effect by metformin could explain the increased antitumor effects observed. Supporting this, in AMPK activating conditions, cell migration/invasion was further impaired in AMPKα(S173C) mutant cells. Metformin emerges as a strong inhibitor of migration/invasion in HCC cells, and glucose restriction potentiates this effect.

更新日期：2019-02-26

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