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A "Patient-Like" Orthotopic Syngeneic Mouse Model of Hepatocellular Carcinoma Metastasis
Published on: October 24, 2015
Metformin and glucose starvation decrease the migratory ability of hepatocellular carcinoma cells: targeting AMPK
Anabela C Ferretti1, Florencia Hidalgo1, Facundo M Tonucci1
1Institute of Experimental Physiology, CONICET, School of Biochemical Sciences, University of Rosario, Rosario, Argentina.
Abstract:
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.
Insights
Metformin and glucose restriction inhibit hepatocellular carcinoma (HCC) cell migration and invasion by activating AMP-activated kinase (AMPK). This combination therapy shows promise for treating this aggressive cancer.
Area of Science:
- Oncology
- Molecular Biology
- Metabolic Signaling
Background:
- Hepatocellular carcinoma (HCC) is a deadly cancer with high metastatic potential.
- AMP-activated kinase (AMPK) is downregulated in HCC and its activation can induce apoptosis.
- Metformin activates AMPK and inhibits HCC cell proliferation, but its effect on invasiveness is unclear.
Purpose of the Study:
- To investigate the effect of metformin and glucose starvation on HCC cell migration and invasion.
- To elucidate the role of AMPK and PKA in metformin's anti-invasive effects.
- To assess the impact of AMPK activation loop mutations on HCC invasiveness.
Main Methods:
- Studied HCC cell migration and invasion under metformin and glucose starvation.
- Analyzed cell viability, proliferation, differentiation, and AMPK/PKA activation.
- Assessed invasiveness in mutants of the AMPKα activation loop.
Main Results:
- Metformin decreased HCC cell migration, invasion, and epithelial-mesenchymal transition.
- Glucose deprivation potentiated the antitumor effects of metformin.
- Metformin activated AMPK and inhibited PKA, with enhanced effects under glucose starvation.
- AMPKα(S173C) mutant cells showed further impaired migration/invasion.
Conclusions:
- Metformin is a potent inhibitor of HCC cell migration and invasion.
- Glucose restriction enhances metformin's anti-invasive effects.
- The metformin-induced reduction in PKA's inhibitory effect on AMPK contributes to its antitumor actions in HCC.
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