Apoptotic signaling pathways ceramides

Ceramides have long been known to be intimately involved in apoptotic signaling pathways [540]. Ceramides induce cytochrome c release via ceramide channel formation [541] or activate Ca -dependent proteases, calpains [542]. Our laboratory were the first to show that Cd " increases ceramide formation, possibly via de novo synthesis, which activates calpain activity by increasing cytosolic Ca ". Apoptosis was then executed in a caspase-independent manner [542]. Interestingly, ceramide and its metabolites are also implicated in multidrug resistance and evasion of apoptosis in tumor cells (see Section 5.8). Active calpains cleave a wide array of substrates that can lead to apoptosis as well as survival and autophagy [543]. Apoptotic substrates include caspases, Bcl-2, Bax, and AIF. In Cd -treated cells, calpains are activated at early time points (3-6 hours) and provide a point for crosstalk with caspases, which are activated later (24 hours) [522] and can also cleave Bax to release cytochrome c [528]. 

An additional regulatory pathway for this process is the system involved in the production of ceramide, which not only mediates apoptotic signals in some cells, but can also modulate apoptosis itself. 

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