Defective Protein Kinase Increases Likelihood of Cancer Development

Cancer researchers have identified the protein kinase C-zeta (PKC-zeta) gene and its encoded protein as being responsible for the suppression of the Ras oncogene, which is deregulated in 20% to 30% of all human cancers.

Ras proteins function as binary molecular switches that control intracellular signaling networks. Signal pathways that are controlled by Ras regulate such processes as actin cytoskeletal integrity, proliferation, differentiation, cell adhesion, apoptosis, and cell migration. Ras dysregulation, a characteristic of many types of cancer cells, leads to increased invasion and metastasis and decreased apoptosis.

Investigators at the University of Cincinnati (OH, USA) sought to chart the molecular pathway and identify the interim steps linking PKC-zeta activity to Ras dysfunction. For this endeavor, they used a line of mice that had been genetically engineered to lack the PKC-zeta gene. They reported in the January 2009 issue of the journal Molecular and Cellular Biology that the PKC-zeta-deficient mice displayed increased Ras-induced lung carcinogenesis. Ras-transformed PKC-zeta-deficient lung cells and embryo fibroblasts produced increased amounts of interleukin-6 (IL-6), which played an essential role in the ability of Ras-transformed cells to grow under nutrient-deprived conditions in vitro and in a mouse xenograft system in vivo.

"These interim steps are critical because they help us determine how best to intervene and stop cancer growth along the way,” explained senior author Dr. Jorge Moscat, professor of cell biology at the University of Cincinnati. "Right now, cancer therapy is delivered with a sledgehammer, and it needs to be more like a scalpel so we avoid unnecessary harm to the body.”

"PKC-zeta would normally slow down Ras transformation and put the brakes on tumor development, but when PKC-zeta is missing or inactive as a result of genetic alterations, tumor growth actually accelerates,” said Dr. Moscat. "Until now, we did not know the specific chain of events that led to Ras-induced lung cancer. Our study fills in important missing information that will enhance our overall understanding of how lung cancer tumors grow and spread.”

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