Diacylglycerol Signaling

22 PKCd as a Target for Chemotherapeutic Drugs
22.3.3 Role of PKCd in Cell Proliferation and Cell
Cycle Regulation
PKCd has been shown to regulate cell proliferation in a cell-specific manner
(Jackson and Foster 2004). Although most studies report that PKCd negatively
regulates cell proliferation and cell cycle progression, there are some studies that
demonstrated that PKCd can also promote cell proliferation. A negative effect of
PKCd on CHO cell proliferation was reported (Watanabe et al. 1992). Similarly,
Mischak et al. and Acs et al. reported that PKCd inhibited the proliferation of
NIH3T3 cells (Acs et al. 2000; Mischak et al. 1993). Interestingly, the inhibitory
effect of PKCd was dependent on its phosphorylation of tyrosine 155 since mutation
in this tyrosine residue increased cell proliferation.
PKCd effects have also been examined in glioma cells. In these cells, PKCd
and PKCa played opposite effects, where PKCa promoted cell proliferation and
PKCd decreased it. Using PKC chimeras it was found that the regulatory domain
of PKCd mediated the inhibitory effect of PKCd on cell proliferation.
The effects of PKCd on the proliferation of breast cancer cells are controversial.
On the one hand, PKCd has been shown to mediate the antiproliferative effects of
inositol hexaphosphate in MCF-7 cells via inhibition of Erk1/2 and pRb (Vucenik
et al. 2005). Similarly, a PKCd-KD mutant abolished the G1 arrest of SKRB-3
breast cancer cells induced by phorbol esters (Yokoyama et al. 2005). In contrast,
other studies implicated PKCd as a positive regulator of breast cancer cells via the
activation of the Ras/Erk1/2 pathway (Keshamouni et al. 2002). In addition, overexpression
of PKCd in immortalized mammary cells induced anchorage-independent
growth and enhanced the survival of the cells, supporting a role of PKCd in promoting
cell proliferation and tumor progression in these cells (Kiley et al. 1999a). A positive
effect of PKCd was also demonstrated for the proliferation signals of the insulinlike
growth factor-1 (IGF-1) receptor in transformed cells via the association and
tyrosine phosphorylation of this isoform (Li et al. 1998).
In addition to its effect on cell proliferation, there have been numerous studies
demonstrating the effect of PKCd on cell cycle progression in both normal and
cancer cells, and PKCd has been shown to arrest cells in G1/S and G2/M phases of
the cell cycle. In lung adenocarcinoma cells, PKCd induced a G1 arrest via upregulation
of the cell cycle inhibitor p21 (Nakagawa et al. 2005). PKCd blocked vascular
smooth muscle cells in G0/G1 phase and prevented progression to S phase of
capillary endothelial cells (Ashton et al. 1999). G1 block was also demonstrated in
A431 cells treated with an antitumor somatostatin analog (Stetak et al. 2001).
PKCd mediated the induction of the G1 cyclin-dependent kinase inhibitor p21 cip1 in
various cell types and inhibit the expression of cyclin D1 (Cerda et al. 2006;
Fukumoto et al. 1997). A recent study showed that PKCd mediated the effect of
PMA on the inhibition of proliferation and cell cycle progression at the G1/S phase
of thyroid cancer cells via an increase in p21 cip1 and p27kip1 (Afrasiabi et al. 2008).
A similar inhibitory effect of PKCd on cell proliferation and G1 arrest in thyroid
cancer cells was also observed (Hung et al. 2008; Koike et al. 2006). In lung cancer
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