Diacylglycerol Signaling

442 C. Brodie and S.L. Lomonaco
Thus, the catalytic domain of PKCd does not play a critical role in cisplatin-induced
apoptosis of small-cell lung cancer cells H69 (Persaud et al. 2005) but did affect
the apoptotic response to glioma cells. The activation of PKCd by cisplatin involved
phosphorylation on tyrosine 332 by Src (Lu et al. 2007b) and PKCd-mediated cisplatin
apoptotic effect occurred via activation of Erk1/2 (Basu and Tu 2005).
Doxorubicin and related compounds: Doxorubicin is an anthracyclin that exerts
major antitumor effects and is used in the treatment of various human cancers. The
intracellular effect of this drug includes the formation of free radicals, inhibition of
topoisomerase II, and DNA intercalation (Muller et al. 1998). These effects lead to
the inhibition of DNA replication and DNA strand break damage (Gewirtz 1999).
The apoptotic effect of doxorubicin appears to mediate its main antiproliferative
effect, and it has been shown to involve the activation of PKCd. Panaretakis et al.
(2005) identified PKCd as a novel substrate of caspase 2 in doxorubicin-treated
leukemic cells and showed that the apoptotic effect of PKCd was mediated by JNK.
In a recent study, PKCd triggered TP53-dependent cell apoptosis in doxorubicintreated
leukemia and osteosarcoma cells (Liu et al. 2007a). In this cellular system,
PKCd increased the transcription of TP53 via the TP53 core promoter element
(CPE-TP53). PKCd interacted and activated the death promoting transcription factor
Btf to co-occupy CPE-TP53.
The C1b domain of PKCd has been recently identified as the molecular target of
a new extranuclear-targeted anthracycline derivative, N-benzyladtiamycin-14valerate
(AD198). Ad198 promoted a rapid translocation of PKCd to the mitochondria
and the phosphorylation of phospholipids scramblase 3 (PLS3) on Thr21,
which mediated the apoptotic role of PKCd in AD198 effect (He et al. 2005).
Docetaxel: The role of PKCd in the effect of docetaxel was studied in melanoma
cells, where it was mediated by c-jun-NH2-terminal kinase (JNK) and inhibited by
the Erk1/2 pathway (Mhaidat et al. 2007). PKCd and PKCe have been found to
mediate the sensitivity and resistance of melanoma cells to docetaxel, respectively.
The pro-apoptotic effect of PKCd was upstream of the JNK pathway in these cells
(Mhaidat et al. 2007).
IFN-a: The cytokine IFN-a, which is routinely used in the treatment of chronic
myelogenous leukemia (CML), induces antileukemic effect in BCR-ABL expressing
cells by the activation of PKCd, which phosphorylates Stat1 and activates IFN-a
inducible gene transcription (Kaur et al. 2005).
In a recent study, PKCd together with Erk and JNK, downstream of PI3-kinase and
mTOR have been shown to mediate the effect of IFN-a on cell apoptosis in multiple
myeloma cells in the absence of de-novo transcription (Panaretakis et al. 2008).
Aplidin: Aplidin is a new antitumor drug currently in phase-II clinical trials with
both in vitro and in vivo activity against cancer cells. Aplidin induces oxidative
stress that results in the phosphorylation of JNK, p38, and Erk and the activation of
the mitochondrial death pathway (Garcia-Fernandez et al. 2002). In addition,
Aplidin induces cleavage of PKCd late in the apoptotic pathway, which acts as an
important component in the activation of the caspase cascade and in the execution
of the apoptotic pathway.