Diacylglycerol Signaling

380 L. Xiao
(SCLC) and nonsmall cell lung cancer (NSCLC). SCLC represents ~20% of all lung
cancer worldwide. The remaining 80% of lung cancers fall into one of three major
subtypes of NSCLC carcinomas: adenocarcinoma, squamous cell carcinoma (SCC),
and large cell carcinoma (LCC). Tobacco smoking is the most important cause of
lung cancer with 80–90% of the disease arising in cigarette smokers. Early epidemiologic
studies of the smoking-caused lung cancer indicated that squamous cell
carcinoma was the most frequently diagnosed type of lung cancer, followed by small
cell carcinoma. Adenocarcinoma of the lung is the most common histologic type of
lung cancer in the world today, and is the most frequent type of lung cancer in
women, nonsmokers, and in young people (Josen et al. 2002; Minna et al. 2002).
SCLC is distinct from NSCLC in biology and clinicopathology. SCLCs are
neuroendocrine (NE) tumors that are strongly smoking-associated and are characterized
by early metastasis and initial marked responsiveness to chemotherapy and
radiation. However, nearly all patients with SCLC relapse and develop resistance to
cytotoxic therapies. The overall 5-year survival rate is only 3–8% (Facchini and
Spiro 1999; Rathore and Weitberg 2002). NSCLCs, at large, are lacking of
neuroendocrine features. They respond poorly to chemotherapy as compared to
SCLCs. The treatment strategies of NSCLCs are based on the stage of the disease
at the time of diagnosis, which include surgery, chemotherapy, radiotherapy, or
combined therapy (Weitberg 2002). Despite significant efforts to improve patient
survival, the overall treatment results have been disappointing. Over the past 30
years, the 5-year lung cancer survival rate remains between 8 and 14%.
In the past decade, an increasing understanding of the pathogenesis of lung
cancer at the cellular and molecular levels has provided significant insights into the
molecular process underlying lung carcinogenesis and the progression of lung
cancer. Lung cancer arises as the result of multiple genetic lesions due to exposure
to cigarette smoke or other environmental carcinogens as well as inherited
predisposition(s) (Hecht 1999; Alberg and Samet 2003). It is becoming clear that
genetic changes acquired by lung cancer are complex and heterogeneous. NSCLC
and SCLC exhibit distinct but overlapping patterns of genetic and epigenetic alterations.
These abnormalities include chromosomal deletion and/or amplification,
epigenetic changes in DNA methylation, the activation of protooncogenes and
other growth-promoting genes, and the inactivation of tumor suppressor genes
(Osada and Takahashi 2002; Sekido et al. 2003; Xiao 2006). The knowledge of the
molecular characteristics of lung cancers has started a novel era in the development
of new compounds that target cancer-specific genetic and molecular alterations and
their associated signal transduction pathways (Auberger et al. 2006).
19.1.2 Protein Kinase C
Protein kinase C (PKC) is a family of ubiquitously expressed, structurally related,
phospholipid-dependent serine/threonine protein kinases which play crucial roles
in transducing signals that regulate diverse biological functions, including proliferation,
transformation, differentiation, and apoptosis (Nishizuka 1995; Dempsey et al. 2000).