Diacylglycerol Signaling

10 Atypical PKCs, NF-kB, and Inflammation
activity in hepatocytes (Sakurai et al. 2006), thus preventing the inflammatory
response and the increased proliferation of the surviving hepatocytes provoked by
the Kupffer cells. Clearly, all of these findings suggest that the role played by
NF-kB and its regulators in tumor initiation and progression will greatly depend on
the tissue and the cell type involved. As general paradigms have not yet emerged
on this question, it is essential to understand the function of the different signaling
cascades in specific tumor types to advance our comprehension of the etiopathogenesis
of cancer.
10.3.2 The aPKC Network in the NF-kB Cancer Paradigm:
Its Role in Lung Cancer
Aberrant activation of NF-kB is strongly associated with cancer. That is, NF-kB is
abnormally activated in many kinds of tumors, including pancreatic cancer, breast
cancer, gastric carcinoma, prostate cancer, and lung cancer. This, and NF-kB’s
known antiapoptotic activity, suggests that NF-kB is a logical therapeutic target for
research on cancer treatment. Additionally, it has been shown that NF-kB is an
important player in preventing apoptotic death after DNA-damaging treatments,
such as chemotherapy and irradiation, clearly affecting the efficacy of these
treatments.
10.3.2.1 The aPKC Adapter, p62, is Critical for Ras-Induced Lung Cancer
Lung cancer is the leading cause of cancer deaths throughout the world, and current
treatments do not lead to a cure for most patients with this type of neoplasia. Targeted
antitumor therapies are likely to prove more effective, but their development will
require a better understanding of the signaling cascades involved. Ras oncogenes are
frequently mutated in human cancers where they play an unquestionably important
role in the genesis and progression of the disease (Downward 2003). In lung adenocarcinomas,
mutations in Ras are present in at least 25% of cases (Bos 1989), suggesting
that the components of Ras-related signaling pathways are promising
candidates for therapeutic targets in lung cancer treatment. The ability of Ras to promote
cell survival is essential for the suppression of apoptosis associated with Rasinduced
transformation and, therefore, for cancer initiation and progression (Hanahan
and Weinberg 2000). Previous studies showed that Ras activates NF-kB, which is
important for cell survival and tumor transformation because it suppresses p53independent
Ras-induced cell death (Mayo et al. 1997). This is a key event because
the final outcome of the oncogenic process is determined by a finely tuned balance
between cell survival and death (Luo et al. 2005). However, the mechanism by which
Ras controls NF-kB activation remains unclear. IKK activation by Ras requires the
combined action of extracellular signal-regulated kinase (ERK) and Akt signals,
although how these translate into IKK activation has not been determined (Arsura
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