Tumour suppression by apoptotic Caspases

Caspases are the main enzymes that initiate and execute cell death by apoptosis. Our work has focussed on functional analysis of caspase-2, one of the first caspases discovered and has identified the apoptotic and non-apoptotic functions of this caspase. I was part of the team that described the function of caspase-2 in apoptosis induced by cytotoxic drugs that disrupt the cytoskeleton (Ho et al. 2008, Oncogene). This was followed by the first seminal demonstration that caspase-2 acts as a tumour suppressor in mice  (Ho et al., 2009, Proc Natl Acad Sci USA). These findings led to further studies using various different mouse tumour models to define the role of caspase-2 in tumour suppression. In particular, the mouse thymoma model (Atm knockout mice) was used to demonstrate genetic interaction between Atm and caspase-2 in tumour suppression and enhanced tumour development in a caspase-2 knockout background (Puccini et al., 2013, Proc Natl Acad Sci USA). Interestingly, I also demonstrated that loss of caspase-2 can in fact delay tumour onset in a MYCN transgenic neuroblastoma mouse model (Dorstyn et al., 2014, Cell Death Dis). These findings indicated that caspase-2 has very defined tissue specific and context specific roles in tumour suppression and we are currently investigating the mechanisms by which it mediates these opposing functions.

Regulation of cellular stress pathways

• Caspase-2 function in genomic stability: My studies have demonstrated that loss of the caspase-2 gene leads to increased proliferation of primary fibroblasts, enhanced cell immortalisation and the accumulation of cells with DNA damage and aneuploidy (abnormal chromosome number) that drives genome instability (Dorstyn et al., 2012, Cell Death Differ). These studies also demonstrated that caspase-2 acts upstream of the tumour suppressor protein p53 in the DNA damage response pathway. Loss of caspase-2 significantly reduces p53 activation levels while stabilising c-Myc levels and our current work is aimed at understanding these roles.  In further studies published in two recent papers (Dawar et al., 2017, Oncogene; Dawar et al., 2016, Cell Death Dis) we report that caspase-2 is essential for the efficient removal of cells carrying mitotic aberrations, especially those with abnormal nuclei or aneuploidy. We discovered that cells that lack caspase-2 have abnormal cell division “checkpoints” that normally prevent damaged cells from surviving and becoming aneuploid. As a consequence, ageing mice that are deficient in caspase-2 accumulate aneuploid cells in their tissues (e.g. bone marrow, spleen, liver) with ageing. These findings indicate that caspase-2 plays a critical role in preventing the long-term survival and growth of cells that could otherwise become malignant, thus proving a mechanism for tumour suppression by this caspase. 

• Caspase-2 regulation of oxidative stress and ageing: In a paper published in Oncogene (Shalini et al., 2015), we demonstrated that caspase-2 deficiency exacerbates cellular stress in mice following low dose challenge with the potent reactive oxygen species (ROS) generator, paraquat (PQ). This was shown to be due to increased inflammation and impaired response to oxidative stress, including failure to upregulate the antioxidant defence mechanism in animals lacking caspase-2. Interestingly, we found that Casp2-/- mice exhibited more severe lung and liver lesions with extensive karyomegaly, a feature commonly associated with ageing and genomic instability. Thus, our work indicates that caspase-2 is critical in regulating the oxidative stress response and in preventing cellular stress and pre-mature ageing. We also made the direct demonstration that the absence of caspase-2 function and activity, accelerates oxidative stress-induced chronic liver cancer (hepatocellular carcinoma) as well as age-related chronic liver inflammation and HCC (Shalini et al., 2016, Cell Death Differ; Dorstyn et al., 2025 under review).

By preventing genomic instability and regulating the oxidative stress response, caspase-2 acts as a key cell surveillance protein and as a consequence is important to prevent tissue dysfunction and pre-mature ageing in mice. We are currently interested in understanding the molecular basis of these mechanisms in healthy ageing, maintaining normal tissue function and role in age-related diseases, including cancer.