Dual induction of apoptosis and senescence in cancer cells by Chk2 activation: Checkpoint activation as a strategy against cancer

作者：Chen CR; Wang WX; Rogoff HA; Li XT; Mang W; Li CJ^*

来源：Cancer Research, 2005, 65(14): 6017-6021.

DOI：10.1158/0008-5472.CAN-05-0677

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 Thr 611, 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.

• 出版日期2005-7-15