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Am. J. Respir. Cell Mol. Biol., Volume 26, Number 5, May, 2002 558-564

Selective p38 Activation in Human Non-Small Cell Lung Cancer

Alissa K. Greenberg, Sharmila Basu, Jing Hu, Ting-an Yie, Kam Meng Tchou-Wong, William N. Rom, and Theodore C. Lee

Division of Pulmonary and Critical Care Medicine, Departments of Medicine, Environmental Medicine, Biochemistry, and the Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York, New York

The mitogen-activated protein kinase (MAPK) pathways transmit signals from the cell membrane to the nucleus. Activation of MAPK cascades may play a role in malignant transformation. We hypothesized that enhanced expression of one or more of these pathways would occur in human lung cancers. Using Western blot analysis of tissue homogenates from resected non- small cell lung cancers and matched non-neoplastic lung tissue, we determined that only activated p38 was consistently increased in tumor compared with normal tissue. In vitro kinase assays confirmed that the levels of activated MAPK correlated with the activity of the enzymes, and immunohistochemical analysis confirmed the cellular localization of the activated MAPKs. We incubated a lung cancer cell line in a hypoxic chamber to simulate the hypoxic environment in solid lung tumors, but found no increase in p38 activation. Contrary to our expectations, ERK and JNK, the MAPK pathways traditionally associated with cell growth and perhaps malignant transformation, were not consistently activated in the human lung tumor samples. However, p38, a MAPK usually associated with stress responses, growth arrest, and apoptosis, was activated in all of the human lung cancer samples, suggesting an additional role for this pathway in malignant cell growth or transformation.

Abbreviations: activator protein-1, AP-1; activating transcription factor, ATF; adenosine triphosphate, ATP; 3,3' diaminobenzidine tetrahydrochloride, DAB; dithiothreitol, DTT; epidermal growth factor receptor, EGFR; extracellular regulated kinase, ERK; mitogen-activated protein, MAP; MAP kinase, MAPK; MAPK kinase, MEK; stress-activated protein kinases, SAPK.




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