PIDDosome-independent tumor suppression by Caspase-2

Abstract

The PIDDosome, a multiprotein complex constituted of the ‘p53-induced protein with a death domain (PIDD), ‘receptor-interacting protein (RIP)-associated ICH-1/CED-3 homologous protein with a death domain' (RAIDD) and pro-Caspase-2 has been defined as an activating platform for this apoptosis-related protease. PIDD has been implicated in p53-mediated cell death in response to DNA damage but also in DNA repair and nuclear factor kappa-light-chain enhancer (NF-κB) activation upon genotoxic stress, together with RIP-1 kinase and Nemo/IKKγ. As all these cellular responses are critical for tumor suppression and deregulated expression of individual PIDDosome components has been noted in human cancer, we investigated their role in oncogenesis induced by DNA damage or oncogenic stress in gene-ablated mice. We observed that Pidd or Caspase-2 failed to suppress lymphoma formation triggered by γ-irradiation or 3-methylcholanthrene-driven fibrosarcoma development. In contrast, Caspase-2 showed tumor suppressive capacity in response to aberrant c-Myc expression, which did not rely on PIDD, the BH3-only protein Bid (BH3 interacting domain death agonist) or the death receptor ligand Trail (TNF-related apoptosis-inducing ligand), but associated with reduced rates of p53 loss and increased extranodal dissemination of tumor cells. In contrast, Pidd deficiency associated with abnormal M-phase progression and delayed disease onset, indicating that both proteins are differentially engaged upon oncogenic stress triggered by c-Myc, leading to opposing effects on tumor-free survival.

Caspase-2 as a tumour suppressor

“…40 Consistent with in vitro studies demonstrating a defective G2/M checkpoint in caspase-2-deficient cells, an increased mitotic index has been observed in caspase-2-deficient tumours derived from Em-Myc and MMTV transgenic mice. 33,34 These findings provide evidence for increased proliferation and impaired cell cycle progression in caspase-2-deficient tumours, suggesting that caspase-2 may regulate these processes in vivo.…”

“…15 These results with Em-Myc/Casp2 À / À mice have been confirmed by independent studies from another laboratory. 33 Interestingly, loss of even a single allele of caspase-2 is sufficient to augment lymphomagenesis in this model, suggesting that caspase-2 may be a haploinsufficient tumour suppressor. 15 These observations are consistent with the reduced expression of caspase-2 in human cancer, which may also be potentially associated with loss of heterozygosity.…”

“…However, caspase-2 failed to suppress tumorigenesis induced by ionizing radiation or 3-methylcholanthrene. 33 These findings suggest that caspase-2 is not a general tumour suppressor and may indicate a contextspecific function for this caspase.…”

“…23 In line with these findings, caspase-2-deficient tumours from mice have been shown to display an increased proliferation rate (unpublished data). 33,34 Therefore, disruptions in pathways controlling growth and proliferation may account, at least in part, for the increased tumorigenic potential of Casp2 À / À MEFs (Figure 2). …”

“…Caspase-2 has also been implicated in the regulation of the G2/M checkpoint, [32][33][34] which promotes G2 arrest and subsequent inhibition of mitotic entry in the presence of unrepaired DNA damage. 40 Inappropriate mitotic progression in cells harbouring DNA breaks has been shown to cause aberrant mitoses leading to aneuploidization via improper chromosome attachment and segregation.…”