Prostate cancer cells are characterised by rapid growth, proliferation and migration, which requires rewiring of cellular metabolism including increased lipid and protein synthesis. AMP-activated protein kinase (AMPK) is a conserved master regulator of energy homeostasis and acts to downregulate anabolism and cell growth, whilst upregulating catabolism to maintain cellular ATP levels. Whether these actions inhibit or aid cancer progression is controversial. Intriguingly, an upstream activating kinase of AMPK, calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ) has recently been implicated in prostate cancer progression.
A small-molecule direct activator of AMPK, 991, was used to test the effects of AMPK activation in a panel of prostate cancer cell lines. AMPK activation led to downregulation of cellular proliferation, 2D migration, invasion and lipogenesis, and upregulation of adhesion in all cell lines. However, in PC3 and 22RV1 cells AMPK activation led to an increase in migration down a chemoattractant gradient. This increase in migration was dependent on CaMKKβ and PAK1 activity.
To investigate the role of AMPK and CaMKKβ in vivo the PTEN prostate cancer mouse model was used. AMPKβ1 and CaMKKβ were deleted in this model creating two novel mouse lines. Upon β1-deletion prostate cancer development was increased based on the timing of a switch in protein expression characterised in the PTEN-/- prostate upon disease progression and pathological analysis of tissue sections. In contrast, disease progression was significantly reduced upon CaMKKβ-deletion in the PTEN-/- prostate based on prostate weight, Ki-67 staining and pathological analysis. Disease progression was also inhibited in the PTEN mouse model upon treatment with a pharmacological inhibitor of CaMKKβ, STO609. These data suggest that AMPK and CaMKKβ have different roles in prostate cancer development and progression likely lie on separate pathways in this disease.