Adipose Triglyceride Lipase Is a Therapeutic Target in Advanced Prostate Cancer That Promotes Metabolic Plasticity.

TitleAdipose Triglyceride Lipase Is a Therapeutic Target in Advanced Prostate Cancer That Promotes Metabolic Plasticity.
Publication TypeJournal Article
Year of Publication2024
AuthorsAwad D, Cao PHong Anh, Pulliam TL, Spradlin M, Subramani E, Tellman TV, Ribeiro CF, Muzzioli R, Jewell BE, Pakula H, Ackroyd JJ, Murray MM, Han JJ, Leng M, Jain A, Piyarathna B, Liu J, Song X, Zhang J, Klekers AR, Drake JM, Ittmann MM, Coarfa C, Piwnica-Worms D, Farach-Carson MC, Loda M, Eberlin LS, Frigo DE
JournalCancer Res
Date Published2024 Mar 04
KeywordsAnimals, Calcium-Calmodulin-Dependent Protein Kinase Kinase, Humans, Lipase, Lipid Metabolism, Lipolysis, Male, Mice, Prostatic Neoplasms, Castration-Resistant, Serine, Tumor Microenvironment

UNLABELLED: Lipid metabolism plays a central role in prostate cancer. To date, the major focus has centered on de novo lipogenesis and lipid uptake in prostate cancer, but inhibitors of these processes have not benefited patients. A better understanding of how cancer cells access lipids once they are created or taken up and stored could uncover more effective strategies to perturb lipid metabolism and treat patients. Here, we identified that expression of adipose triglyceride lipase (ATGL), an enzyme that controls lipid droplet homeostasis and a previously suspected tumor suppressor, correlates with worse overall survival in men with advanced, castration-resistant prostate cancer (CRPC). Molecular, genetic, or pharmacologic inhibition of ATGL impaired human and murine prostate cancer growth in vivo and in cell culture or organoids under conditions mimicking the tumor microenvironment. Mass spectrometry imaging demonstrated that ATGL profoundly regulates lipid metabolism in vivo, remodeling membrane composition. ATGL inhibition induced metabolic plasticity, causing a glycolytic shift that could be exploited therapeutically by cotargeting both metabolic pathways. Patient-derived phosphoproteomics identified ATGL serine 404 as a target of CAMKK2-AMPK signaling in CRPC cells. Mutation of serine 404 did not alter the lipolytic activity of ATGL but did decrease CRPC growth, migration, and invasion, indicating that noncanonical ATGL activity also contributes to disease progression. Unbiased immunoprecipitation/mass spectrometry suggested that mutation of serine 404 not only disrupts existing ATGL protein interactions but also leads to new protein-protein interactions. Together, these data nominate ATGL as a therapeutic target for CRPC and provide insights for future drug development and combination therapies.

SIGNIFICANCE: ATGL promotes prostate cancer metabolic plasticity and progression through both lipase-dependent and lipase-independent activity, informing strategies to target ATGL and lipid metabolism for cancer treatment.

Alternate JournalCancer Res
PubMed ID38038968
PubMed Central IDPMC10939928
Grant ListP30 CA016672 / CA / NCI NIH HHS / United States
P50 CA140388 / CA / NCI NIH HHS / United States
S10 OD026804 / OD / NIH HHS / United States
P01 CA098912 / CA / NCI NIH HHS / United States
P42 ES027725 / ES / NIEHS NIH HHS / United States
P50 HD103555 / HD / NICHD NIH HHS / United States
P30 ES030285 / ES / NIEHS NIH HHS / United States
P30 CA125123 / CA / NCI NIH HHS / United States
R01 CA184208 / CA / NCI NIH HHS / United States
Related Faculty: 
Massimo Loda, M.D. Hubert Pakula, Ph.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
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