Activated checkpoint kinase 2 provides a survival signal for tumor cells.
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.
Ghosh
Jagadish C
JC
Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Dohi
Takehiko
T
Raskett
Christopher M
CM
Kowalik
Timothy F
TF
Altieri
Dario C
DC
D000230:Adenocarcinoma; D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology*; D064447:Checkpoint Kinase 2; D003110:Colonic Neoplasms; D004249:DNA Damage; D004789:Enzyme Activation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011471:Prostatic Neoplasms; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection; D014183:Transplantation, Heterologous
D034741:RNA, Small Interfering; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases