Chk1 Suppresses a Caspase-2 Apoptotic Response to DNA Damage that Bypasses p53, Bcl-2, and Caspase-3

Abstract

Evasion of DNA damage-induced cell death, via mutation of the p53 tumor suppressor or overexpression of prosurvival Bcl-2 family proteins, is a key step toward malignant transformation and therapeutic resistance. We report that depletion or acute inhibition of checkpoint kinase 1 (Chk1) is sufficient to restore gamma-radiation-induced apoptosis in p53 mutant zebrafish embryos. Surprisingly, caspase-3 is not activated prior to DNA fragmentation, in contrast to classical intrinsic or extrinsic apoptosis. Rather, an alternative apoptotic program is engaged that cell autonomously requires atm (ataxia telangiectasia mutated), atr (ATM and Rad3-related) and caspase-2, and is not affected by p53 loss or overexpression of bcl-2/xl. Similarly, Chk1 inhibitor-treated human tumor cells hyperactivate ATM, ATR, and caspase-2 after gamma-radiation and trigger a caspase-2-dependent apoptotic program that bypasses p53 deficiency and excess Bcl-2. The evolutionarily conserved "Chk1-suppressed" pathway defines a novel apoptotic process, whose responsiveness to Chk1 inhibitors and insensitivity to p53 and BCL2 alterations have important implications for cancer therapy.

Caspase-2 as a tumour suppressor

“…Checkpoint kinase 1 (Chk1) was shown to suppress a caspase-2-dependent apoptosis pathway in p53-deficient cells. 37 Chk1 inhibition restored sensitivity to gamma-radiation-induced apoptosis independent of mitochondrial involvement and caspase-3. 37 This pathway is dependent on the ataxia telangiectasia-mutated (ATM) kinase, which upon activation by DNA damage phospho rylates the p53-induced death domain protein (PIDD), triggering the RIP-associated protein with a death domain (RAIDD) recruitment and assembly of the PIDDosome complex, leading to caspase-2 activation.…”

“…37 Chk1 inhibition restored sensitivity to gamma-radiation-induced apoptosis independent of mitochondrial involvement and caspase-3. 37 This pathway is dependent on the ataxia telangiectasia-mutated (ATM) kinase, which upon activation by DNA damage phospho rylates the p53-induced death domain protein (PIDD), triggering the RIP-associated protein with a death domain (RAIDD) recruitment and assembly of the PIDDosome complex, leading to caspase-2 activation. 38 This Chk1-suppressed pathway has been proposed to be a mechanism of apoptosis that ensures deletion of cells that sustain DNA damage in the presence of compromised checkpoint surveillance.…”

“…38 This Chk1-suppressed pathway has been proposed to be a mechanism of apoptosis that ensures deletion of cells that sustain DNA damage in the presence of compromised checkpoint surveillance. 37,38 Importantly, these findings highlight that some potentially unidentified functions of caspase-2 may become apparent only under very specific experimental or physiological conditions. Caspase-2 has been shown to affect the function of multiple proteins that are known to regulate cell proliferation and apoptosis (Figure 2).…”

Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

“…Sidi et al (2008) reported that replication stress after DSB activates a different pathway where Chk1 suppresses a caspase-2-dependent apoptotic pathway. Chk1 inhibition hyperactivates ATM, ATR and caspase-2 after g-radiation and triggers a caspase-2-dependent apoptotic program that bypasses p53 deficiency and excess Bcl2 (Sidi et al, 2008). In addition, caspasemediated cleavage of Chk1 during apoptosis leads to enhanced apoptotic reactions (Okita et al, 2007;Matsuura et al, 2008).…”

Knockdown of Checkpoint Kinase 1 Is Associated with the Increased Radiosensitivity of Glioblastoma Stem-Like Cells

“…In addition, Chk1 and Chk2 may be associated with the occurrence of glioma (Sancer et al 2004). Moreover, previous studies reported that loss of Chk1 sensitizes tumor cells to many anticancer agents (Wang et al 2004;Sidi et al 2008;Monica et al 2008;Morgan et al 2010). All these above mentioned suggest the key role of Chk1 and Chk2 enzymes in the cell cycle checkpoints activation, which in turn promotes the DNA damage repairing (Bao et al 2006), thereby preventing the cells from radiation and chemical therapy associated death.…”