AMPK activation by oncogenesis is required to maintain cancer cell proliferation in astrocytic tumors.
5'-AMP-activated protein kinase (AMPK) is an energy sensor that controls cell metabolism, and it has been related to apoptosis and cell-cycle arrest. Although its role in metabolic homeostasis is well documented, its function in cancer is much less clear. In this study, we examined the role of AMPK in a mouse model of astrocytoma driven by oncogenic H-Ras(V12) and/or with PTEN deletion based on the common constitutive activation of the Raf/MEK/ERK and PI3K/AKT cascades in human astrocytomas. We also evaluated the activity and role of AMPK in human glioblastoma cells and xenografts. AMPK was constitutively activated in astrocytes expressing oncogenic H-Ras(V12) in parallel with high cell division rates. Genetic deletion of AMPK or attenuation of its activity in these cells was sufficient to reduce cell proliferation. The levels of pAMK were always related to the levels of phosphorylated retinoblastoma (Rb) at Ser804, which may indicate an AMPK-mediated phosphorylation of Rb. We confirmed this AMPK-Rb relationship in human glioblastoma cell lines and xenografts. In clinical specimens of human glioblastoma, elevated levels of activated AMPK appeared especially in areas of high proliferation surrounding the blood vessels. Together, our findings indicate that the initiation and progression of astrocytic tumors relies upon AMPK-dependent control of the cell cycle, thereby identifying AMPK as a candidate therapeutic target in this setting.
Departamento de Fisioloxía, CIMUS, Facultade de Medicina, Universidade de Santiago de Compostela, Santiago de Compostela, Spain.
Marcos
M
Ríos
Marc
M
Foretz
Benoit
B
Viollet
Angel
A
Prieto
Máximo
M
Fraga
Jose A
JA
Costoya
Rosa
R
Señarís
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001254:Astrocytoma / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D015870:Gene Expression; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D021381:Protein Transport; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D011720:Pyrazoles; D011743:Pyrimidines; C516138:dorsomorphin; D055372:AMP-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras)