Diacylglycerol Signaling

22 PKCd as a Target for Chemotherapeutic Drugs
and the cleavage of PKCd suggesting that PKCd may also act upstream of caspase
3 and pointing to the existence of a positive regulatory loop (Blass et al. 2002).
PKCd undergoes cleavage in response to various antitumor drugs such as etoposide
(Blass et al. 2002; Reyland et al. 1999), cisplatin (Li et al. 2007), cytosine arabinoside
(Koriyama et al. 1999), and mitomycin (Emoto et al. 1996). The cleavage of
PKCd generates a catalytic fragment that is constitutively active and which has
been shown to promote cell apoptosis when localized to the nucleus or mitochondria.
Although the cleavage of PKCd has been mainly associated with the apoptotic
function of PKCd, it can also provide antiapoptotic signals particularly when it is
not localized to the nucleus (Okhrimenko et al. 2005). The cleavage of PKCd
has been shown to be modulated by its tyrosine phosphorylation, especially tyrosines
311 and 332 that flank the caspase cleavage site of this isoform. Indeed,
tyrosine 311 was essential for the cleavage of PKCd by oxidative stress (Kaul et al.
2005), whereas tyrosine 332 was important for the cleavage of PKCd by cisplatin
in glioma cells (Lu et al. 2007b).
22.4.2 Role of PKCd in the Response of Tumor Cells
to Chemotherapeutic Drugs
Etoposide: The topoisomerase II inhibitor, etoposide, is an important chemotherapeutic
agent that is used to treat a wide spectrum of tumors (Meresse et al. 2004). Various
studies demonstrated the role of PKCd in mediating the apoptotic effect of etoposide
in various cell types. Etoposide induces tyrosine phosphorylation of PKCd, caspase-
3-dependent cleavage, and its translocation to the nucleus, which are essential for its
apoptotic effect (Blass et al. 2002; DeVries-Seimon et al. 2007). In a recent study, the
proapoptotic effect of PKCd in etoposide-treated glioma cells was shown to be mediated
by Erk1/2. The phosphorylation of PKCd on tyrosines 64 and 187 induced the
ubiquitination and proteosomal degradation of MKP-1, which resulted in prolonged
Erk1/2 activation and cell apoptosis (Lomonaco et al. 2008). Shin et al. (2004) demonstrated
that etoposide induced transcriptional and posttranscriptional regulation of
the PKCd gene in murine leukemic cells that were dependent on the activation of
PKCd, suggesting a mechanism of autoregulation of PKCd.
Cisplatin: PKCd has been shown to mediate the apoptotic effect of cisplatin and
related compounds in various tumor cells. The sensitivity of small cell lung cancer
cells and ovarian carcinoma cells was associated with an increase in the expression
of PKCd and a decrease in the expression of classical PKC isoforms (Basu et al.
1996). cis-Diamminedichloroplatinum (II) (cDDP) induced translocation of PKCd to
the cytosol and heavy membrane and its cleavage and inhibition of PKCd blocked
cDDP-induced cell apoptosis at an early stage that preceded caspase activation (Basu
et al. 2001). In gastric cancer cells, PKCd increased the sensitivity of the cells to
cisplatin when it was overexpressed with p53 (Iioka et al. 2005). The importance
of PKCd cleavage in the apoptotic response of cancer cells to cisplatin is cell dependent.
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