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

Brown MF, Leibowitz BJ, Chen D, He K, Zou F, Sobol RW, Beer-Stolz D, Zhang L, Yu J
Cell Death Dis. 2015 6: e1729

PMID: 25906152 · PMCID: PMC4650537 · DOI:10.1038/cddis.2015.104

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.

MeSH Terms (11)

Caspase 3 Cell Death Colonic Neoplasms DNA Damage HCT116 Cells HEK293 Cells HT29 Cells Humans Nuclear Pore Complex Proteins RNA-Binding Proteins Transfection

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