2. Academic Validation
  3. v-Src Oncogene Induces Trop2 Proteolytic Activation via Cyclin D1

v-Src Oncogene Induces Trop2 Proteolytic Activation via Cyclin D1

  • Cancer Res. 2016 Nov 15;76(22):6723-6734. doi: 10.1158/0008-5472.CAN-15-3327.
Xiaoming Ju 1 2,  Xuanmao Jiao 1 2,  Adam Ertel 1 2,  Mathew C Casimiro 1 2,  Gabriele Di Sante 1 2,  Shengqiong Deng 1 2,  Zhiping Li 1 2,  Agnese Di Rocco 1 2,  Tingting Zhan 2 3,  Adam Hawkins 2 4,  Tanya Stoyanova 5,  Sebastiano Andò 6,  Alessandro Fatatis 2 7,  Michael P Lisanti 2 8,  Leonard G Gomella 2 9,  Lucia R Languino 1 2,  Richard G Pestell 10 2 4
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
  • 2 Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
  • 3 Division of Biostatistics, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania.
  • 4 Department of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania.
  • 5 Department of Microbiology, Immunology, and Molecular Genetics University of California, Los Angeles, California.
  • 6 Faculty of Pharmacy, Nutrition, and Health Science, University of Calabria, Arcavacata, Rende CS, Italy.
  • 7 Department of Pharmacology and Physiology and Laboratory Medicine, Drexel University, Philadelphia, Pennsylvania.
  • 8 Stem Cell Biology and Regenerative Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania.
  • 9 Department of Urology, Thomas Jefferson University, Philadelphia, Pennsylvania.
  • 10 Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. [email protected].
PMID: 27634768 DOI: 10.1158/0008-5472.CAN-15-3327
Abstract

Proteomic analysis of castration-resistant prostate Cancer demonstrated the enrichment of Src tyrosine kinase activity in approximately 90% of patients. Src is known to induce cyclin D1, and a cyclin D1-regulated gene expression module predicts 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). Patients with prostate Cancer with increased nuclear Trop2 ICD and cyclin D1, and reduced Numb, had reduced recurrence-free survival probability (HR = 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 Res; 76(22); 6723-34. ©2016 AACR.

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