This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chen, C.-R. Articles by Li, C. J. Search for Related Content PubMed PubMed Citation Articles by Chen, C.-R. Articles by Li, C. J.

Dual Induction of Apoptosis and Senescence in Cancer Cells by Chk2 Activation: Checkpoint Activation as a Strategy against Cancer

Departments of ¹ Oncology Lead Discovery and ² Target Research, ArQule Biomedical Institute, ArQule, Inc., Norwood, Massachusetts

Requests for reprints: Chiang J. Li, ArQule Biomedical Institute, Norwood, MA 02062. Phone: 781-278-0900; Fax 781-278-0975; E-mail: mmalak{at}arqule.com.

The human checkpoint kinase 2 (Chk2) plays a central role in regulation of the cellular response to DNA damage, resulting in cell cycle arrest, DNA repair, or apoptosis depending on severity of DNA damage and the cellular context. Chk2 inhibitors are being developed as sensitizers for chemotherapeutic agents. In contrast, here we report that direct activation of Chk2 alone (without chemotherapeutic agents) led to potent inhibition of cancer cell proliferation. In the absence of de novo DNA damage, checkpoint activation was achieved by increased Chk2 expression, as evidenced by its phosphorylation at Thr⁶⁸, resulting in senescence and apoptosis of cancer cells (DLD1 and HeLa). The Chk2-induced apoptosis was p53 independent and was mediated by caspase activation triggered by loss of mitochondrial potential. The Chk2-induced senescence was also p53 independent and was associated with induction of p21. These results suggest that direct activation of checkpoint kinases may be a novel approach for cancer therapy.

This article has been cited by other articles:

				Bin Zhang, Xiubin Gu, U. Uppalapati, M. A. Ashwell, D. S. Leggett, and C. J. Li High-Content Fluorescent-Based Assay for Screening Activators of DNA Damage Checkpoint Pathways J Biomol Screen, July 1, 2008; 13(6): 538 - 543. [Abstract] [PDF]

				U. Murzik, P. Hemmerich, S. Weidtkamp-Peters, T. Ulbricht, W. Bussen, J. Hentschel, F. von Eggeling, and C. Melle Rad54B Targeting to DNA Double-Strand Break Repair Sites Requires Complex Formation with S100A11 Mol. Biol. Cell, July 1, 2008; 19(7): 2926 - 2935. [Abstract] [Full Text] [PDF]

				G. Buscemi, L. Carlessi, L. Zannini, S. Lisanti, E. Fontanella, S. Canevari, and D. Delia DNA Damage-Induced Cell Cycle Regulation and Function of Novel Chk2 Phosphoresidues Mol. Cell. Biol., November 1, 2006; 26(21): 7832 - 7845. [Abstract] [Full Text] [PDF]

				H. T. Yip, R. Chopra, R. Chakrabarti, M. S. Veena, B. Ramamurthy, E. S. Srivatsan, and M. B. Wang Cisplatin-Induced Growth Arrest of Head and Neck Cancer Cells Correlates With Increased Expression of p16 and p53. Arch Otolaryngol Head Neck Surg, March 1, 2006; 132(3): 317 - 326. [Abstract] [Full Text] [PDF]

				C.-M. Aliouat-Denis, N. Dendouga, I. Van den Wyngaert, H. Goehlmann, U. Steller, I. van de Weyer, N. Van Slycken, L. Andries, S. Kass, W. Luyten, et al. p53-Independent Regulation of p21Waf1/Cip1 Expression and Senescence by Chk2 Mol. Cancer Res., November 1, 2005; 3(11): 627 - 634. [Abstract] [Full Text] [PDF]