Diacylglycerol Signaling

14 PKC–PKD Interplay in Cancer
activation, which may be relevant to epithelial tumor cell survival (Cowell et al.
2009). Besides NF-kB, PKC/PKD may target additional pathways including the
downregulation of JNK and p38 and/or the upregulation of EKR1/2 and Akt to promote
cell survival (Buder-Hoffmann et al. 2009; Chen et al. 2008; Song et al. 2009;
Wang et al. 2004). Among them, the suppression of the JNK signaling is especially
compelling. JNK plays a crucial role in mediating apoptotic signaling induced by
stress factors, inflammatory cytokines, and genotoxic agents. PKD was first found to
attenuate epidermal growth factor (EGF) signaling to JNK (Bagowski et al. 1999;
Hurd and Rozengurt 2001). Later, it was found that PKD formed complex with JNK
and phosphorylated alternative sites in N-terminus of c-Jun (now identified as S58) to
suppress the phosphorylation of c-Jun by JNK and modulate AP-1 transcriptional
activity (Hurd et al. 2002; Waldron et al. 2007).
An interesting observation is that PKD1 can be cleaved by caspase-3 during
apoptosis induced by 1-b-D-arabinofuranosylcytosine (ara-C) and other genotoxic
agents (cisplatin, etoposide, and doxorubicin) in tumor cells (U-937 or A431)
(Endo et al. 2000; Vantus et al. 2004). The cleavage generates active PKD1 catalytic
fragments (59 and 62 kDa in case of doxorubicin treatment) (Vantus et al.
2004). However, although the cleaved catalytic fragment of PKD1 is not sufficient
to induce apoptosis when overexpressed, it sensitizes tumor cells to DNA damageinduced
apoptosis (Endo et al. 2000). This finding suggests that increased PKD1
expression may benefit chemotherapy by enhancing chemosensitivity of tumor
cells, implying that PKD may be pro-apoptotic under certain conditions. Assessing
the functional relevance of the cleavage at an endogenous level, such as selective
blockade of the cleavage, may bring more insights.
14.4.3 Adhesion, Migration, and Invasion
Cell adhesion, migration, and invasion play important roles in tumor initiation,
progression, and metastasis. For a cancer cell to metastasize, it is required to escape
from the primary tumor, enter the circulation, arrest in the microcirculation, invade
and grow in a secondary tissue compartment. This complex multistep process is
dependent on many properties of a tumor cell including adhesion, migration, invasion,
activities of proteases, survival and growth, and many regulatory components
need to act in a highly concerted manner to drive a cell to move and invade. PKD
plays an essential role in the control of cell motility and invasion. Accumulating
evidence indicate that PKD promotes cell motility at multiple levels, and isoforms
of PKD are differentially implicated. In fibroblasts, PKD regulates cell migration
through at least two important processes, trafficking and integrin signaling. It has
been demonstrated that PKD1 modulates fibroblast locomotion and localized Rac1dependent
leading edge activity by affecting anterograde membrane traffic from the
TGN to the plasma membrane (Prigozhina and Waterman-Storer 2004). PKD1 also
has been shown to regulate cell motility by promoting avb3 integrin recycling and
delivery to nascent focal adhesions (Woods et al. 2004). These functions of PKD
coincide with its major role as a protein/membrane trafficking regulator. Besides
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