Expression of coxsackie and adenovirus receptor distinguishes transitional cancer states in therapy-induced cellular senescence

P C Wu,D Y Wu,Q Wang,Z M Dong,E Chu,I C Ivanova,R S Roberson

doi:10.1038/cddis.2010.47

P C Wu, D Y Wu + Show 5 more

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https://doi.org/10.1038/cddis.2010.47

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Journal: Cell Death & Disease	Publication Date: Sep 1, 2010
Citations: 14	License type: cc-by

Affiliation: VA Puget Sound Health Care System

Abstract

Therapy-induced cellular senescence describes the phenomenon of cell cycle arrest that can be invoked in cancer cells in response to chemotherapy. Sustained proliferative arrest is often overcome as a contingent of senescent tumor cells can bypass this cell cycle restriction. The mechanism regulating cell cycle re-entry of senescent cancer cells remains poorly understood. This is the first report of the isolation and characterization of two distinct transitional states in chemotherapy-induced senescent cells that share indistinguishable morphological senescence phenotypes and are functionally classified by their ability to escape cell cycle arrest. It has been observed that cell surface expression of coxsackie and adenovirus receptor (CAR) is downregulated in cancer cells treated with chemotherapy. We show the novel use of surface CAR expression and adenoviral transduction to differentiate senescent states and also show in vivo evidence of CAR downregulation in colorectal cancer patients treated with neoadjuvant chemoradiation. This study suggests that CAR is a candidate biomarker for senescence response to antitumor therapy, and CAR expression can be used to distinguish transitional states in early senescence to study fundamental regulatory events in therapy-induced senescence.

Highlights

Therapy-induced cellular senescence has been shown in a variety of in vitro and in vivo models and in human tumor samples.[1,13,14,15,16] Despite the inactivation of p53 and p16INK4a/
In chemotherapy-treated senescent p53-null and p16-deficient NCI-H1299 cells, we have shown that senescence escape is closely associated with the aberrant over-expression of the cyclin-dependent kinase Cdc2/Cdk1.19 In an effort to gain a better understanding of this biological barrier, we sought to further characterize early events during senescence escape
We show that surface Coxsackie and adenovirus (Adv) receptor (CAR) downregulation is a consistent feature observed in multiple cell lines during chemotherapy-induced senescence

Summary

Introduction

Therapy-induced cellular senescence has been shown in a variety of in vitro and in vivo models and in human tumor samples.[1,13,14,15,16] Despite the inactivation of p53 and p16INK4a/. In chemotherapy-treated senescent p53-null and p16-deficient NCI-H1299 cells, we have shown that senescence escape is closely associated with the aberrant over-expression of the cyclin-dependent kinase Cdc2/Cdk1.19 In an effort to gain a better understanding of this biological barrier, we sought to further characterize early events during senescence escape. This is the first descriptive report of the isolation and characterization of two distinct transitional states in chemotherapy-induced senescence distinguished by the ability of senescent cells to escape cell cycle arrest. Our work proposes CAR as a novel biomarker for senescence in response to antitumor therapy, and that surface CAR expression may be a means for isolating distinct transitional states within therapy-induced senescence whose biological differences may yield novel insights into barriers of senescence

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