Poster Presentation 30th Lorne Cancer Conference 2018

Illuminating the role of caspase 3 deletions in human colorectal cancer (#155)

Meg Elliott , Anuratha Sakthianandeswaren , Dimitri Mouradov , Oliver M Sieber

The caspase 3 gene is located within a region of significant focal loss on chromosome 4q in human colorectal cancer (CRC), however whether caspase 3 deletion contributes to carcinogenesis is unknown. Caspase 3 is a cysteine protease involved in the execution phase of apoptosis, responsible for the cleavage of structural and DNA repair proteins, leading to cell death. A preliminary small interfering RNA (siRNA) screen revealed that caspase 3 knock-down resulted in an increase in CRC cell viability. To determine the functional consequence of caspase 3 deletions in human CRC, cell death and viability assays were performed and revealed that caspase 3 knock-down conferred an increased resistance to spontaneous apoptosis and confirmed the increased viability phenotype observed in the initial siRNA screen.

Persistent cGAS/STING pathway activation has been shown to contribute to the development of cancer, probably through cytokines, chemokines and growth factors that stimulate cellular proliferation and survival, as well as by promoting angiogenesis. Investigation of the cGAS/STING cytoslic DNA sensing pathway activation upon caspase 3 knock-down did not contain sufficient evidence to support the hypothesis that this pathway was active in caspase 3 deficient CRC cell lines.

Resistance of tumour cells to undergo cell death is a central hallmark of cancer, promoting tumour growth and attenuating responses to cancer therapies. The clinical relevance of caspase 3 loss in CRC cell lines was assessed in regards to their response to standard-of-care CRC chemotherapeutics (5-fluorouracil, irinotecan and oxaliplatin) and BH3 mimetic drugs. Our analysis revealed that caspase 3 knock-down conferred increased resistance to BH3 mimetic drugs but not standard-of-care chemotherapeutic agents.

In summary, caspase 3 is frequently deleted in human CRC. This deletion may confer a survival advantage to CRCs through increasing resistance to intrinsic apoptosis and/or alterations in cell proliferation. This phenotype may be of clinical importance with respect to tumour treatment response, in particular with respect to pro-survival Bcl-2 family inhibitors which may in the future be considered for the treatment of CRC.