Caspases and cancer

Abstract

Evasion of apoptosis is considered to be one of the hallmarks of human cancers. This cell death modality is executed by caspases and several upstream regulatory factors, which direct their proteolytic activity, have been defined as either tumor suppressors or oncogenes. Often these regulatory factors, in addition to being potent apoptosis inducers, function in cell survival or repair signaling pathways in response to cellular stress. Thus, loss of function in a distinct regulatory mechanism does not necessarily mean that tumor formation is due to apoptosis malfunction resulting from insufficient caspase activation. Although each caspase has been assigned a distinct role in apoptosis, some redundancy with respect to their regulatory functions and substrate recognition is evident. Jointly, these proteases could be considered to possess solid tumor suppressor function, but what is the evidence that deregulation of specific caspases per se induces inappropriate cell survival, leading to enhanced tumorigenic potential? This question will be addressed in this review, which covers basic molecular mechanisms derived from in vitro analyses and emphasizes new insights that have emerged from in vivo and clinical studies.

Figure 1

Overview of caspase cascades and their inhibitors

Figure 2

Upstream regulatory pathways leading to apoptosis, cell cycle arrest, DNA repair and proliferation