UMMS Affiliation

Department of Cancer Biology; Department of Molecular Genetics and Microbiology

Date

12-21-2006

Document Type

Article

Subjects

Adenocarcinoma; Animals; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Colonic Neoplasms; *DNA Damage; Enzyme Activation; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Mice, SCID; Prostatic Neoplasms; Protein-Serine-Threonine Kinases; RNA, Small Interfering; Transfection; Transplantation, Heterologous

Disciplines

Cancer Biology | Microbiology | Molecular Genetics

Abstract

Tumor cells often become resistant to DNA damage-based therapy; however, the underlying mechanisms are not yet understood. Here, we show that tumor cells exposed to DNA damage counteract cell death by releasing the antiapoptotic protein, survivin, from mitochondria. This is independent of p53, and requires activated checkpoint kinase 2 (Chk2), a putative tumor suppressor. Molecular or genetic targeting of Chk2 prevents the release of survivin from mitochondria, enhances DNA damage-induced tumor cell apoptosis, and inhibits the growth of resistant in vivo tumors. Therefore, activated Chk2 circumvents its own tumor-suppressive functions by promoting tumor cell survival. Inhibiting Chk2 in combination with DNA-damaging agents may provide a rational approach for treating resistant tumors.

Rights and Permissions

Citation: Cancer Res. 2006 Dec 15;66(24):11576-9. Link to article on publisher's site

DOI of Published Version

10.1158/0008-5472.CAN-06-3095

Related Resources

Link to article in PubMed

Journal Title

Cancer research

PubMed ID

17178848

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.