Loss of Caspase-3 sensitizes colon cancer cells to genotoxic stress via RIP1-dependent necrosis

被引：47

作者：

Brown, M. F. ^{[1
,2
]}

Leibowitz, B. J. ^{[1
,2
]}

Chen, D. ^{[2
,3
]}

He, K. ^{[1
,2
]}

Zou, F. ^{[2
,3
]}

Sobol, R. W. ^{[2
,3
]}

Beer-Stolz, D. ^{[1
,2
]}

Zhang, L. ^{[2
,3
]}

Yu, J. ^{[1
,2
]}

机构：

[1] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15213 USA

[2] Univ Pittsburgh, Inst Canc, Hillman Canc Ctr Res Pavil, Pittsburgh, PA 15213 USA

[3] Univ Pittsburgh, Dept Pharmacol & Chem Biol, Sch Med, Pittsburgh, PA 15213 USA

来源：

CELL DEATH & DISEASE | 2015年 / 6卷

关键词：

PROGRAMMED NECROSIS; DNA-DAMAGE; APOPTOSIS; DEATH; INHIBITOR; PUMA; NECROPTOSIS; KINASE; RIP3; BAX;

D O I：

10.1038/cddis.2015.104

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

Caspase-3 is the best known executioner caspase in apoptosis. We generated caspase-3 knockout (C3KO) and knockdown human colorectal cancer cells, and found that they are unexpectedly sensitized to DNA-damaging agents including 5-fluorouracil (5-FU), etoposide, and camptothecin. C3KO xenograft tumors also displayed enhanced therapeutic response and cell death to 5-FU. C3KO cells showed intact apoptosis and activation of caspase-7 and -9, impaired processing of caspase-8, and induction of necrosis in response to DNA-damaging agents. This form of necrosis is associated with HMGB1 release and ROS production, and suppressed by genetic or pharmacological inhibition of RIP1, MLKL1, or caspase-8, but not inhibitors of pan-caspases or RIP3. 5-FU treatment led to the formation of a z-VAD-resistant pro-caspase-8/RIP1/FADD complex, which was strongly stabilized by caspase-3 KO. These data demonstrate a key role of caspase-3 in caspase-8 processing and suppression of DNA damage-induced necrosis, and provide a potentially novel way to chemosensitize cancer cells.

引用

页码：e1729 / e1729

页数：10

共 43 条

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American Cancer Society, 2013, CANC FACTS FIG 2013

[2]

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