Diacylglycerol Signaling

18 PKC and Prostate Cancer
may be critical for regulating normal cytokinesis. Direct phosphorylation substrates
of PKCbII were not studied here. Further research is needed to clarify the role of
PKCbII-pericentrin interaction in prostate cancer cell proliferation and to determine
if the phenotype seen here involves PKCbII substrates. Another possibility is
that receptor for active C kinases (RACK1) may be positively regulating prostate
cancer cell proliferation when PKCbII is bound to RACK1 (i.e., in activated
PKCbII) by interacting with AR (Rigas et al. 2003).
Another PKC isozyme that plays important roles in mitogenic signaling in prostate
cancer cells is PKCe. PKCe plays a critical role in the transition of androgendependent
LNCaP cells into androgen-independent cells and also increases cell
proliferation (Wu et al. 2002). Overexpression of PKCe in LNCaP cells enabled
LNCaP cells to proliferate in the absence of androgens or serum. Cell cycle analysis
revealed that PKCe overexpression increases the number of cells in S phase and
accelerates G1/S transition (Wu et al. 2002). Elevated levels of Raf-1 and ERK 1/2
phosphorylation are observed in PKCe-overexpressing cells, as well as high levels
of phosphorylated RB, cyclins D1, cyclin D3, and cyclin E. These cells also present
increased levels of c-myc (Wu et al. 2002). Taken together, these studies suggest
that PKCe is an active regulator of the ERK and RB signaling in LNCaP cells to
promote proliferation.
18.4 PKC Isozymes in Apoptosis and Cell Survival
A remarkable feature of androgen-sensitive prostate cancer cell lines, such as
LNCaP, C4-2, and CWR22-Rv1 cells, is that they undergo apoptosis in response to
phorbol esters. This was initially shown by Day et al. and subsequently by several
other groups (Day et al. 1994; Xiao et al. 2009). Analysis of the PKC isozymes
involved in this response revealed an important role for PKCd. Indeed cell death
induced by phorbol 12-myristate 13-acetate (PMA) in LNCaP cells can be inhibited
by expression of a dominant-negative PKCd mutant as well as by PKCd depletion
using RNAi (Gavrielides et al. 2006). Moreover, overexpression of PKCd in LNCaP
cells markedly enhances the apoptotic response of PMA. Induction of LNCaP cell
apoptosis by PKCd does not involve its proteolytic cleavage, as described in many
other cell types, suggesting that it depends on allosteric activation of the enzyme
upon translocation to the plasma membrane (Fujii et al. 2000). It is interesting that
androgen-independent prostate cancer cells such as PC-3 or DU-145 do not undergo
apoptosis in response to phorbol esters, although growth inhibition is observed
(Sugibayashi et al. 2002). Studies have also revealed that PKCd also mediates prostate
cancer cell death by chemotherapeutic agents. Etoposide and paclitaxel induced
apoptosis through ceramide formation in LNCaP and DU145 cells, and inhibition
of PKCd significantly blocks ceramide formation and apoptosis in LNCaP cells
(Sumitomo et al. 2002). Ceramide leads to the translocation of PKCd to mitochondria,
causing cytochrome c release and caspase-9 activation (Sumitomo et al. 2002).
Therefore, PKCd is a crucial mediator of apoptosis induced by phorbol esters or
anticancer drugs.
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