Diacylglycerol Signaling

23 Atypical PKCs as Targets for Cancer Therapy
23.6 Transcriptional Targets of Oncogenic aPKC Signaling
The expression of matrix metalloproteinase-9 (MMP9) correlates with the progression
in gliomas (Rao et al. 1993) and inhibition of MMP9 significantly reduces
the invasiveness of glioma cells in vitro and in vivo (Kondraganti et al. 2000).
In glioma cells, IL-6 and TNFa induce activation of PKCz leading to an
NFkB-mediated increase in MMP9 expression (Esteve et al. 2002). Our recent
work has identified another member of the MMP family, MMP10 or stromelysin 2,
as a major transcriptional target of oncogenic PKCi/Par6 signaling in NSCLC cells
and primary NSCLC tumors (Frederick et al. 2008). MMP10 was identified as a
potential transcriptional target of PKCi through genome-wide gene expression
analysis of NSCLC cells expressing either a control lentiviral RNAi or an RNAi
that specifically knocks down PKCi expression (Frederick et al. 2008). Analysis of
primary NSCLC samples revealed that MMP10 is overexpressed in NSCLC and
that MMP10 expression correlates positively with PKCi expression (Frederick
et al. 2008). Depletion of PKCi, Par6, or Rac1 by RNAi inhibits MMP10 expression
in NSCLC cells. Futhermore, expression of exogenous wild-type Par6 in Par6 KD
cells restored MMP10 expression whereas expression of Par6 mutants that either
cannot bind PKCi or Rac1 did not. Similar to depletion of PKCi and Par6, RNAi
mediated knockdown of MMP10 blocks anchorage-independent growth and cell
invasion in NSCLC cells. In addition, loss of transformed growth and invasion in
PKCi KD or Par6 KD NSCLC cells is rescued by the addition of catalytically
active MMP10. Thus, expression of MMP10 is regulated through the PKCi-Par6-
Rac1 signaling axis and MMP10 represents a key downstream effector in PKCimediated
transformation in lung cancer cells. The molecular mechanisms by which
PKCi-mediated overexpression of MMP10 leads to transformation is unclear and
merits further investigation.
In order to identify other potential downstream targets of oncogenic PKCi, we
recently conducted a meta-analysis of gene expression in primary lung adenocarcinomas
(LAC) from three independent public domain databases (Erdogan et al.
2009). Using these data, we identified genes whose expression correlates with that
of PKCi in primary LAC tumors. Seven genes were identified whose expression
was coordinately induced with PKCi expression in all three databases (Erdogan et al.
2009). QPCR analysis of a panel of 60 primary LAC samples showed that four of
these seven genes were highly overexpressed in tumors compared to matched normal
control lung tissue, and that expression of each of these four genes exhibited a
strong positive correlation with PKCi expression (Erdogan et al. 2009). RNAimediated
knock down of PKCi in three LAC cell lines led to significant reduction
in expression of each of the four target genes, indicating that PKCi regulates the
expression of these four genes in LAC cells (Erdogan et al. 2009). RNAi-mediated
knock down of each of these genes led to significant inhibition of anchorageindependent
growth and cellular invasion demonstrating that each of them are
important for transformation in LAC cells (Erdogan et al. 2009). Furthermore, several
of these PKCi-regulated genes are coordinately overexpressed with PKCi in
other major tumor types including lung squamous cell carcinoma, breast, colon,
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