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Caspase-2 protects against oxidative stress in vivo

Oncogene volume 34, pages 4995–5002 (2015)Cite this article

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Abstract

Caspase-2 belongs to the caspase family of cysteine proteases with established roles in apoptosis. Recently, caspase-2 has been implicated in nonapoptotic functions including maintenance of genomic stability and tumor suppression. Our previous studies demonstrated that caspase-2 also regulates cellular redox status and delays the onset of several ageing-related traits. In the current study, we tested stress tolerance ability in caspase-2-deficient (Casp2−/−) mice by challenging both young and old mice with a low dose of the potent reactive oxygen species (ROS) generator, PQ that primarily affects lungs. In both groups of mice, PQ induced pulmonary damage. However, the lesions in caspase-2 knockout mice were consistently and reproducibly more severe than those in wild-type (WT) mice. Furthermore, serum interleukin (IL)-1β and IL-6 levels were higher in PQ-exposed aged Casp2−/− mice indicating increased inflammation. Interestingly, livers from Casp2−/− mice displayed karyomegaly, a feature commonly associated with ageing and aneuploidy. Given that Casp2−/− mice show impaired antioxidant defense, we tested oxidative damage in these mice. Protein oxidation significantly increased in PQ-injected old Casp2−/− mice. Moreover, FoxO1, SOD2 and Nrf2 expression levels were reduced and induction of superoxide dismutase (SOD) and glutathione peroxidase activity was not observed in PQ-treated Casp2−/− mice. Strong c-Jun amino-terminal kinase (JNK) activation was observed in Casp2−/− mice, indicative of increased stress. Together, our data strongly suggest that caspase-2 deficiency leads to increased cellular stress largely because these mice fail to respond to oxidative stress by upregulating their antioxidant defense mechanism. This makes the mice more vulnerable to exogenous challenges and may partly explain the shorter lifespan of Casp2−/− mice.

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Acknowledgements

We thank Jim Manavis for TUNEL, the staff at the SA Pathology animal resource facility for maintaining the mouse strains, and Swati Dawar for help with some of the immunoblots in Figure 4. This work was supported by the National Health and Medical Research Council (NHMRC) project grant (1021456), a Cancer Council Research Fellowship to LD and a NHMRC Senior Principal Research Fellowship (1002863) to SK.

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  1. J Puccini and C H Wilson: These authors contributed equally to this work.

Authors and Affiliations

  1. Centre for Cancer Biology, University of South Australia, Adelaide, SA, Australia

    S Shalini, J Puccini, C H Wilson, L Dorstyn & S Kumar

  2. SA Pathology and School of Medical and Veterinary Science, University of Adelaide, Adelaide, SA, Australia

    J Finnie

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  1. S Shalini
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Correspondence to S Kumar.

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Shalini, S., Puccini, J., Wilson, C. et al. Caspase-2 protects against oxidative stress in vivo. Oncogene 34, 4995–5002 (2015). https://doi.org/10.1038/onc.2014.413

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