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About the Authors:
M. Cecilia Caino
Contributed equally to this work with: M. Cecilia Caino, Cynthia Lopez-Haber
Affiliation: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
Cynthia Lopez-Haber
Contributed equally to this work with: M. Cecilia Caino, Cynthia Lopez-Haber
Affiliation: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
Joseph L. Kissil
Affiliation: Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania, United States of America
Marcelo G. Kazanietz
* E-mail: [email protected]
Affiliation: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
Introduction
Lung cancer is one of the major causes of cancer-related mortality, with more than 220,000 cases diagnosed and 157,000 deaths estimated for 2010 [1], [2]. The genesis of lung cancer involves the progressive appearance of genetic and epigenetic alterations both in oncogenes and tumor-suppressor genes, ultimately leading to deregulated activation of mitogenic and survival signaling pathways. Common alterations in non-small cell lung cancer (NSCLC), the most prevalent form of lung cancer, include mutations in K-Ras, overexpression of epidermal growth factor receptor (EGFR) and Bcl2, as well as inactivation/down-regulation of p53, Rb, and Pten tumor suppressor genes [3]. Accumulating evidence indicates that protein kinase C (PKC) expression and/or activity is considerably altered in human lung cancer [4], although a causal relationship with disease progression remains to be established. The PKC family consists of three classes of serine-threonine kinases with distinct biochemical and regulatory properties: classical/conventional (cPKCs α, β, and γ), novel (nPKCs δ, ε, η, and θ), and atypical (aPKCs ζ and ι). cPKCs and nPKCs are responsive to phorbol esters and the second messenger diacylglycerol (DAG), a product of PIP2 breakdown by phospholipase C (PLC) in response to activation of tyrosine-kinase and G-protein-coupled receptors. PKC isozymes have paradoxical functional roles depending on the cellular context, ranging from apoptosis to survival, and from mitogenesis to cell cycle inhibition [4], [5].
Despite our extensive knowledge on PKC in cancer development, there is surprisingly limited information regarding the role of individual PKC isozymes in lung cancer progression compared to other epithelial cancers such as skin, breast or prostate cancer, where the involvement of PKCs has been extensively documented [6]. A few available...