V-Src Oncogene Induces Trop2 Proteolytic Activation Via Cyclin D1

Overview

Journal Cancer Res

Specialty Oncology

Date 2016 Sep 17

PMID 27634768

Citations 13

Authors

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

Affiliations

Soon will be listed here.

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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