Adipose triglyceride lipase is regulated by CAMKK2-AMPK signaling and drives advanced prostate cancer

Lipid metabolism plays a central role in prostate cancer. To date, the major focus on prostate cancer lipid metabolism has centered on de novo lipogenesis and lipid uptake with little consideration for how cancer cells access these lipids once they are created or taken up and stored. Patient-derived phosphoproteomics identified adipose triglyceride lipase (ATGL), a previously suspected tumor suppressor, as a CAMKK2-AMPK signaling target that, conversely, promotes castration-resistant prostate cancer (CRPC) progression. Phosphorylation of ATGL increased its lipase activity, cancer cell proliferation, migration, and invasion. Shotgun lipidomics and mass spectrometry imaging demonstrated ATGL’s profound regulation of lipid metabolism in vitro and in vivo , remodeling membrane composition. Inhibition of ATGL induced metabolic plasticity, causing a glycolytic shift that could be exploited therapeutically by co-targeting both metabolic pathways. Together, these data nominate ATGL and intracellular lipolysis as potential therapeutic targets for the treatment of CRPC and provide insights for future combination therapies. ### Competing Interest Statement D.E.F. has received research funding from GTx, Inc and has familial relationships with Hummingbird Bioscience, Maia Biotechnology, Alms Therapeutics, Hinova Pharmaceuticals, and Barricade Therapeutics. J.M.D. has no conflicts relevant to this work. However, he holds equity in and serves as Chief Scientific Officer of Astrin Biosciences. This interest has been reviewed and managed by the University of Minnesota in accordance with its Conflict-of-Interest policies. L.S.E. is an inventor in patents related to DESI-MS imaging technology, licensed to Waters corporation. The other authors report no potential conflicts of interest. The funders had no role in the conceptualization of the study or writing of the manuscript, or in the decision to publish this article.