Invited Speaker 12th International Meeting on AMPK 2023

The role of AMPK in prostate cancer (#14)

David Carling 1 , Lucy Penfold 1 , Angela Woods 1 , Alice E Pollard 1 , Stuart A Cook 1 2 , Anissa A Widjaja 2
  1. MRC London Institute of Medical Sciences, London, United Kingdom
  2. Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore

Emerging evidence indicates that metabolic dysregulation drives prostate cancer (PCa) progression and metastasis. Here, we show that genetic and pharmacological activation of AMPK provides a protective effect on PCa progression in vivo1. AMPK activation induces PGC1a 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, and show a correlation between this gene network and PGC1a gene expression in human PCa. These preclinical findings support the use of AMPK activators for treatment of PCa to improve patient outcome. In parallel studies, we found that interleukin 11 (IL11) signals to phosphorylate LKB1 at serine 325 and 428, inhibiting the subsequent phosphorylation of AMPK on threonine 1722. Neutralising anti-IL11 antibodies (e.g. BI 765423) are currently in clinical trials for treatment of fibrotic diseases. Taken together, or findings suggest a strategy whereby inhibition of IL11 using anti-IL11 antibodies would lead to activation of LKB1 and AMPK signalling, preventing PCa progression. We are currently testing this hypothesis in a mouse model of metastatic PCa3.

  1. Penfold, L., Woods, A., Pollard, A.E., Arizanova, J., Pascual-Navarro, E., Muckett, P.J., Dore, M.H., Montoya, A., Whilding, C., Fets, L., et al. (2023). AMPK activation protects against prostate cancer by inducing a catabolic cellular state. Cell Rep. 42, 112396.
  2. Widjaja, A.A., Viswanathan, S., Wei Ting, J.G., Tan, J., Shekeran, S.G., Carling, D., Lim, W.W., and Cook, S.A. (2022). IL11 stimulates ERK/P90RSK to inhibit LKB1/AMPK and activate mTOR initiating a mesenchymal program in stromal, epithelial, and cancer cells. iScience 25, 104806.
  3. Arriaga, J.M., S., P., Alshalalfa, M., Zhao, J., Zou, M., Giacobbe, A., Madubata, C.J., Kim, J.Y., Rodriguez, A., Coleman, I., et al. (2020). A MYC and RAS co-activation signature in localized prostate cancer drives bone metastasis and castration resistance. Nat. Cancer 1, 1082-1096.