Selective induction of necrotic cell death in cancer cells by beta-lapachone through activation of DNA damage response pathway.
Most efforts thus far have been devoted to develop apoptosis inducers for cancer treatment. However, apoptotic pathway deficiencies are a hallmark of cancer cells. We propose that one way to bypass defective apoptotic pathways in cancer cells is to induce necrotic cell death. Here we show that selective induction of necrotic cell death can be achieved by activation of the DNA damage response pathways. While beta-lapachone induces apoptosis through E2F1 checkpoint pathways, necrotic cell death can be selectively induced by beta-lapachone in a variety of cancer cells. We found that beta-lapachone, unlike DNA damaging chemotherapeutic agents, transiently activates PARP1, a main regulator of the DNA damage response pathway, both in vitro and in vivo. This occurs within minutes of exposure to beta-lapachone, resulting in selective necrotic cell death. Inhibition of PAR blocked beta-lapachone-induced necrosis. Furthermore, necrotic cell death induced by beta-lapachone was significantly reduced in PARP1 knockout cell lines. Our data suggest that selective necrotic cell death can be induced through activation of DNA damage response pathways, supporting the idea of selective necrotic cell death as a therapeutic strategy to eliminate cancer cells.
Sun
Xiangao
X
Department of Therapeutic Biology, ArQule Biomedical Institute, Norwood, Massachusetts 02062, USA.
Li
Youzhi
Y
Li
Wei
W
Zhang
Bin
B
Wang
A J
AJ
Sun
Jieti
J
Mikule
Keith
K
Jiang
Zhiwei
Z
Li
Chiang J
CJ
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D045744:Cell Line, Tumor; D004249:DNA Damage; D005260:Female; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009285:Naphthoquinones / Q000633:toxicity*; D009336:Necrosis; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D009285:Naphthoquinones; C014638:beta-lapachone; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases