Intracellular signal transduction pathways activated by ceramide and its metabolites

Choline kinase inhibition induces the increase in ceramides resulting in a highly specific and selective cytotoxic antitumoral strategy as a potential mechanism of action

“…A final consequence was a specific drastic increase in the intracellular levels of ceramides in tumour cells in contrast with a mild increase found in the primary cells under similar conditions (Figure 9a, b). This increment in ceramides may result in stress, apoptosis or cell cycle arrest through the ceramides activated effectors (CAE) (Hannun, 1996;Kolesnick, 2002;Ruvolo, 2003). Further studies will assign the specific ceramide-dependent signalling modulators responsible for MN58b effects.…”

PKC α mediates chemoresistance in acute lymphoblastic leukemia through effects on Bcl2 phosphorylation

“…9,28,48 Interestingly, both PKC a and Bcl2 are dephosphorylated by PP2A during stress stimuli, thus suggesting a complex level of regulation of the entire Bcl2 pathway during apoptosis. 25,26 Whether a similar but opposite regulatory mechanism for the Bcl2 pathway during survival conditions exists is currently unknown. Such a novel mechanism may exist, since the overexpression of PKC a in the REH cells results in the suppression of PP2A activity while promoting chemoresistance.…”

“…This finding suggests a complex level of regulation of the entire Bcl2 pathway during apoptosis. [23][24][25][26] Whether a similar but opposite regulatory mechanism for the Bcl2 pathway during survival conditions exists is currently unknown. In this study, we show evidence for such a novel mechanism, since the overexpression of PKC a in the acute lymphoblastic leukemia (ALL)-derived cell line REH results in the suppression of PP2A activity while promoting chemoresistance against the chemotherapeutic drug etoposide.…”

The sphingolipid salvage pathway in ceramide metabolism and signaling

“…Successfully, some ceramide targets have been identified, including PKCζ [52], kinase suppressor of Ras [78], cRaf [51], cathepsin D [79], and CAPPs composed of protein phosphatase 1 (PP1) and protein phosphate 2A (PP2A) [80][81][82]. CAPPs belong to the family of Ser/Thr protein phosphatases, and ceramide has been shown to activate CAPPs leading to the dephosphorylation of various proteins including, Bax, Bcl-2, PKCα, Rb protein, SR protein, and Akt, ultimately modulating/mediating various responses of cells [29,83]. In PKC signaling, ceramide derived from the salvage pathway leads to attenuation/ termination of activation of the p38 MAPK through dephosphorylation.…”