AMPK activation protects against prostate cancer by inducing a catabolic cellular state
Lucy Penfold,
Angela Woods,
Alice E. Pollard,
Julia Arizanova,
Eneko Pascual-Navarro,
Phillip J. Muckett,
Marian H. Dore,
Alex Montoya,
Chad Whilding,
Louise Fets,
Joao Mokochinski,
Theodora A. Constantin,
Anabel Varela-Carver,
Damien A. Leach,
Charlotte L. Bevan,
Alexander Yu. Nikitin,
Zoe Hall,
David Carling
Affiliations
Lucy Penfold
MRC London Institute of Medical Sciences, Hammersmith Hospital Campus, Imperial College London, London W12 0NN, UK; Corresponding author
Angela Woods
MRC London Institute of Medical Sciences, Hammersmith Hospital Campus, Imperial College London, London W12 0NN, UK
Alice E. Pollard
Institute of Clinical Sciences, Imperial College London, London, UK
Julia Arizanova
MRC London Institute of Medical Sciences, Hammersmith Hospital Campus, Imperial College London, London W12 0NN, UK
Eneko Pascual-Navarro
MRC London Institute of Medical Sciences, Hammersmith Hospital Campus, Imperial College London, London W12 0NN, UK
Phillip J. Muckett
MRC London Institute of Medical Sciences, Hammersmith Hospital Campus, Imperial College London, London W12 0NN, UK
Marian H. Dore
MRC London Institute of Medical Sciences, Hammersmith Hospital Campus, Imperial College London, London W12 0NN, UK
Alex Montoya
MRC London Institute of Medical Sciences, Hammersmith Hospital Campus, Imperial College London, London W12 0NN, UK
Chad Whilding
MRC London Institute of Medical Sciences, Hammersmith Hospital Campus, Imperial College London, London W12 0NN, UK
Louise Fets
MRC London Institute of Medical Sciences, Hammersmith Hospital Campus, Imperial College London, London W12 0NN, UK
Joao Mokochinski
MRC London Institute of Medical Sciences, Hammersmith Hospital Campus, Imperial College London, London W12 0NN, UK
Theodora A. Constantin
Imperial Centre for Translational and Experimental Medicine, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK
Anabel Varela-Carver
Imperial Centre for Translational and Experimental Medicine, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK
Damien A. Leach
Imperial Centre for Translational and Experimental Medicine, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK
Charlotte L. Bevan
Imperial Centre for Translational and Experimental Medicine, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK
Alexander Yu. Nikitin
Department of Biomedical Sciences and Cornell Stem Cell Program, Cornell University, Ithaca, NY, USA
Zoe Hall
Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion, and Reproduction, Imperial College London, London, UK
David Carling
MRC London Institute of Medical Sciences, Hammersmith Hospital Campus, Imperial College London, London W12 0NN, UK; Institute of Clinical Sciences, Imperial College London, London, UK; Corresponding author
Summary: Emerging evidence indicates that metabolic dysregulation drives prostate cancer (PCa) progression and metastasis. AMP-activated protein kinase (AMPK) is a master regulator of metabolism, although its role in PCa remains unclear. Here, we show that genetic and pharmacological activation of AMPK provides a protective effect on PCa progression in vivo. We show that AMPK activation induces PGC1α expression, leading to catabolic metabolic reprogramming of PCa cells. This catabolic state is characterized by increased mitochondrial gene expression, increased fatty acid oxidation, decreased lipogenic potential, decreased cell proliferation, and decreased cell invasiveness. Together, these changes inhibit PCa disease progression. Additionally, we identify a gene network involved in cell cycle regulation that is inhibited by AMPK activation. Strikingly, we show a correlation between this gene network and PGC1α gene expression in human PCa. Taken together, our findings support the use of AMPK activators for clinical treatment of PCa to improve patient outcome.
