Understanding new therapeutic paradigms for both castrate-sensitive and more aggressive castrate-resistant prostate cancer is essential to improve clinical outcomes. As a critically important cellular process, autophagy promotes stress tolerance by recycling intracellular components to sustain metabolism important for tumor survival.
To assess the importance of autophagy in prostate cancer, we generated a new autochthonous genetically engineered mouse model (GEMM) with inducible prostate-specific deficiency in the Pten tumor suppressor and autophagy-related-7 (Atg7) genes. Atg7 deficiency produced an autophagy-deficient phenotype and delayed Pten-deficient prostate tumor progression in both castrate-naïve and castrate-resistant cancers. Atg7-deficient tumors display evidence of endoplasmic reticulum (ER) stress, suggesting that autophagy may promote prostate tumorigenesis through management of protein homeostasis. Taken together, these data support the importance of autophagy for both castrate-naïve and castrate-resistant growth in a newly developed GEMM, suggesting a new paradigm and model to study approaches to inhibit autophagy in combination with known and new therapies for advanced prostate cancer.
Genes & development. 2016 Feb 15 [Epub]
Urmila Santanam, Whitney Banach-Petrosky, Cory Abate-Shen, Michael M Shen, Eileen White, Robert S DiPaola
Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA;, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA;, Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA; Department of Urology, Columbia University Medical Center, New York, New York 10032, USA; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York 10032, USA; Department of Systems Biology, Columbia University Medical Center, New York, New York 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York 10032, USA;, Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA; Department of Urology, Columbia University Medical Center, New York, New York 10032, USA; Department of Systems Biology, Columbia University Medical Center, New York, New York 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York 10032, USA; Department of Genetics and Development, Columbia University Medical Center, New York, New York 10032, USA;, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA; Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey 08854, USA. , Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA;