Proteomic analysis of castration-resistant prostate cancer demonstrated the enrichment of SRC tyrosine kinase activity in approximately ninety percent of patients. Src is known to induce cyclin D1, and a cyclin D1-regulated gene expression module predict poor outcome in human prostate cancer. The tumor-associated calcium signal transducer 2 [TACSTD2/Trop2/M1S1] is enriched in the prostate, promoting prostate stem cell self-renewal upon proteolytic activation via a γ-secretase cleavage complex (PS1, PS2) and TACE (ADAM17), which releases the Trop2 intracellular domain (Trop2 ICD). Herein, v-Src transformation of primary murine prostate epithelial cells increased the proportion of prostate cancer stem cells as characterized by gene expression, epitope characteristics and prostatosphere formation. Cyclin D1 was induced by v-Src, and Src kinase induction of Trop2 ICD nuclear accumulation, required cyclin D1. Cyclin D1 induced abundance of the Trop2 proteolytic cleavage activation components (PS2, TACE) and restrained expression of the inhibitory component of the Trop2 proteolytic complex (Numb). Prostate cancer patients with increased nuclear Trop2 ICD and cyclin D1, and reduced Numb, had reduced recurrence-free survival probability (hazard ratio 4.35). Cyclin D1 therefore serves as a transducer of v-Src-mediated induction of Trop2 ICD by enhancing abundance of the Trop2 proteolytic activation complex.
Cancer research. 2016 Sep 15 [Epub ahead of print]
Xiaoming Ju, Xuanmao Jiao, Adam Ertel, Mathew C Casimiro, Gabriele Di Sante, Shengqiong Deng, Zhiping Li, Agnese Di Rocco, Tingting Zhan, Adam Hawkins, Tanya Stoyanova, Sebastiano Ando, Alessandro Fatatis, Michael P Lisanti, Leonard G Gomella, Lucia R Languino, Richard G Pestell
Cancer Biology, Thomas Jefferson University., Pharmacology and Experimental Therapeutics, Thomas Jefferson University., Medical Oncology, Thomas Jefferson University., Microbiology, Immunology, and Molecular Genetics, University of California., Pharmacy and Health and Nutritional Sciences, University of Calabria., Sidney Kimmel Cancer Center, Thomas Jefferson University., The Breakthrough Breast Cancer Research Unit, The University of Manchester., Urology, Thomas Jefferson University., Prostate Cancer Discovery and Development Program, Sidney Kimmel Cancer Center, Thomas Jefferson University., Cancer Biology, Thomas Jefferson University .