Grant: Project Grant

The body relies on a particular cell death program called apoptosis to eliminate defective cells. This program involves the sequential activation of a distinct set of caspases, which are enzymes that cleave and thereby inactivate hundreds of proteins necessary for cell survival. A fundamental trait of cancer cells is their inherent or acquired resistance to apoptosis. This cancer feature often accounts for chemotherapeutic failure and is associated with enhanced tumorigenesis and metastasis. At the molecular level, resistance to apoptosis usually involves a block of death signal transmission from the initiator to the executioner caspases, the latter of which is responsible for killing the cell. As such, a direct consequence of resistance to apoptosis is that tumor cells can uniquely sustain the activity of initiator caspases by avoiding the killing effects of the others. Results from our recent study support the hypothesis that substrate products of initiator caspases contribute to enhancing tumorigenic and metastatic features of apoptosis-resistant cancer cells. The proposed project seeks to validate this postulate by designing a method for detecting the activity of initiator caspases and their cleaved substrates as biomarkers of colorectal cancer progression, by identifying proteins cleaved by initiator caspases in apoptosis-resistant cancer cells, and by verifying the tumorigenic and metastatic properties of these identified substrates in colorectal cancer cell models. Experimental validation of our hypothesis would offer a ground-breaking paradigm shift in the current understanding of the roles of caspases in cell death and when tumor cells become resistant to apoptosis. Notably, our work could lead to the development of new biomarkers and innovative therapies to overcome clinical resistance to several types of current clinically used cancer-death-based chemotherapies.