Caspase-8 as a therapeutic target in cancer

Abstract

Caspase-8 is an apical caspase which initiates programmed cell death following death receptor ligation. This central role in apoptosis has prompted significant clinical interest in regulating caspase-8 expression and proteolytic activity. However, caspase-8 has also been found to play a number of non-apoptotic roles in cells, such as promoting activation NFκB signaling, regulating autophagy and altering endosomal trafficking, and enhancing cellular adhesion and migration. Therefore, depending upon the specific cellular context, caspase-8 may either potentiate or suppress tumor malignancy. Accordingly, a marked heterogeneity exists in the expression patterns of caspase-8 among different tumor types. Therapeutics have been developed which can increase caspase-8 expression, yet it remains unclear whether this approach will be beneficial in all cases. Care is warranted, and the role of caspase-8 should be addressed on a case by case basis.

Src-inducible association of CrkL with procaspase-8 promotes cell migration

“…15 It is also possible that procaspase-8 expression is retained to suppress necrosis, through its capacity to cleave RIPK3. The dis-regulated activity of Src or other tyrosine kinases commonly observed in tumors may be sufficient to suppress caspase-8 proapoptotic functions.…”

“…and this may account, in part, for the continued expression of caspase-8 in many carcinoma. 15 Several mechanistically linked processes are implicated in caspase-8-enhanced cell migration, including the enhancement of tyrosine kinase receptor signaling, the promotion of calpain and Rac1 activity, alterations to integrin trafficking, and crosstalk with the PI3 kinase pathway. 3,9,13 Proteolytic function, which is necessary for apoptosis and the suppression of RIPK3-mediated necrosis, is not required for the regulation of cell migration.…”

Old, new and emerging functions of caspases

“…175 Increased caspase-8 expression has been observed in many advanced-stage tumors suggesting that caspase-8 might promote metastasis. 176 Further evidence in support of its metastatic role comes from the fact that caspase-8 has been shown to interact with the focal adhesion complex, 177 thereby promote cell migration. The complex observations on caspase-8 can be attributed to the fact that this caspase is involved in apoptosis and also protected against necroptosis.…”

Proteases and cytokines as mediators of interactions between cancer and stromal cells in tumours

“…For example, progression of some types of cancer, including glioblastoma, has been associated with a lack of caspase-8 expression. On the other hand, caspase-8 was found to be upregulated in other types of cancers and promotes malignancy probably by its other non-apoptotic functions such as inducing NF-κB signalling, altering endosomal trafficking, regulating autophagy and enhancing cellular adhesion and migration (Stupack 2013).…”