v-Src Oncogene Induces Trop2 Proteolytic Activation via Cyclin D1.

Authors

Xiaoming Ju, Thomas Jefferson UniversityFollow
Xuanmao Jiao, Thomas Jefferson UniversityFollow
Adam Ertel, Thomas Jefferson UniversityFollow
Mathew C. Casimiro, Thomas Jefferson UniversityFollow
Gabriele Disante, Thomas Jefferson UniversityFollow
Shengqiong Deng, Thomas Jefferson UniversityFollow
Zhiping Li, Thomas Jefferson UniversityFollow
Agnese Di Rocco, Thomas Jefferson UniversityFollow
Tingting Zhan, Thomas Jefferson UniversityFollow
Adam Hawkins, Thomas Jefferson UniversityFollow
Tanya Stoyanova, University of California, Los Angeles; Stanford University
Sebastiano Andò, University of CalabriaFollow
Alessandro Fatatis, Thomas Jefferson University; Drexel UniversityFollow
Michael P. Lisanti, Thomas Jefferson University; University of ManchesterFollow
Leonard G. Gomella, Thomas Jefferson UniversityFollow
Lucia R. Languino, Thomas Jefferson UniversityFollow
Richard G. Pestell, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

11-15-2016

Comments

This article has been peer reviewed. It is the authors' final version prior to publication in Cancer Research, Volume 76, Issue 22, November 2016, Pages 6723-6734.

The published version is available at https://doi.org/10.1158/0008-5472.CAN-15-3327 . Copyright © AACR

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.

Recommended Citation

Ju, Xiaoming; Jiao, Xuanmao; Ertel, Adam; Casimiro, Mathew C.; Disante, Gabriele; Deng, Shengqiong; Li, Zhiping; Di Rocco, Agnese; Zhan, Tingting; Hawkins, Adam; Stoyanova, Tanya; Andò, Sebastiano; Fatatis, Alessandro; Lisanti, Michael P.; Gomella, Leonard G.; Languino, Lucia R.; and Pestell, Richard G., "v-Src Oncogene Induces Trop2 Proteolytic Activation via Cyclin D1." (2016). Department of Cancer Biology Faculty Papers. Paper 128.
https://jdc.jefferson.edu/cbfp/128

PubMed ID

27634768

Language

English