Diacylglycerol Signaling

22 PKCd as a Target for Chemotherapeutic Drugs
TRAIL: Tumor necrosis factor-related apoptosis inducing ligand (TRAIL; Apo2
ligand) belongs to the tumor necrosis factor superfamily (Kelley and Ashkenazi
2004) and induces apoptosis in many transformed cells including some glioma cell
lines and primary cultures (Song et al. 2003; Wiley et al. 1995). TRAIL acts by
formation of the death-inducing signaling complex that is also common to other
members of the death receptors.
In contrast to its proapoptotic effect in most antitumor agents, PKCd appears to
mediate the resistance of cancer cells to TRAIL or antiapoptotic effects of TRAIL
in various cellular systems. PKCd induced an increase in FLIP expression, which
acts as a negative regulator of FAS and TRAIL-mediated apoptosis via transactivation
of NF-kB, suggesting that the PKCd/NF-kB pathway plays a major role in the
sensitivity of colon cancer cells to both FAS and TRAIL (Wang, International journal
of cancer, 2007).
In prostate cancer cells, the apoptotic effect of PMA was mediated by a novel
autocrine proapoptotic loop that was triggered by PKCd and involved the release of
death receptor ligand and activation of the extrinsic apoptotic pathway (Gonzalez-
Guerrico and Kazanietz 2005).
In glioma cells, TRAIL induced the phosphorylation of PKCd on tyrosine 155,
its translocation to the ER, and cleavage. Silencing of PKCd increased the sensitivity
of glioma cells to TRAIL, whereas overexpression of PKCd exerted an opposite
effect, suggesting that in these cells, PKCd mediates the antiapoptotic effects of
TRAIL. Interestingly, in this cellular system, the cleavage of PKCd was essential
for its protective effect (Okhrimenko et al. 2005). In a recent study, Ndebele et al.
(2008) demonstrated that exogenous expression of phospholipids scramblase 3
(PLS3) enhances the apoptotic effect of PKCd and that activation of PKCd by
TRAIL mediates changes in cardiolipin induced by PLS3.
22.4.3 PKCd Interacting Proteins and Downstream
Signaling Pathways
Various interacting proteins of PKCd have been identified that mediate the apoptotic
function of PKCd in response to various apoptotic stimuli and chemotherapeutic
drugs. In the mitochondria, PKCd interacts with and phosphorylates scramblase 3
(Liu et al. 2003). Other PKCd targets/substrates are nuclear proteins that function in
cell apoptosis such as DNA-dependent protein kinase (DNA-PK), which plays an
essential role in the repair of DNA double strand breaks and interacts with c-Abl
during genotoxic stress (Bharti et al. 1998). Lamin proteins represent another important
potential target for the apoptotic function of PKCd, which acts as an apoptotic
lamin kinase (Cross et al. 2000). P73 is a p53 homolog, which is also phosphorylated
by PKCd, and this phosphorylation is associated with accumulation of p73b and the
induction of p73b transactivation and apoptotic functions (Ren et al. 2002).
PKCd activates multiple signaling pathways in response to apoptotic stimuli and
chemotherapeutic drugs. In addition to the signaling molecules that were discussed
previously, PKCd activates various members of the MAP kinase family and the
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