Centers

Project Title:  The role of p38 MAPK and NOX in the development of oxidative stress-mediated non-melanoma skin cancer

Principal Investigator: Arianna L. Kim, PhD (Department of Dermatology)

Year: 2009

Award Amount:  $50,000

Abstract:  Non-melanoma skin cancer (NMSC), including squamous cell carcinomas (SCCs), is the most common form of cancer in the United States. Solar ultraviolet B (UVB) radiation is the leading causative agent of NMSC; it creates DNA mutations, produces reactive oxygen species (ROS) in cells, and consequently, deregulates important intracellular components and processes. p38 mitogen-activated protein kinase (MAPK), which is essential for the transduction of extracellular signals into intracellular changes, was recently identified as a sensor protein for ROS. p38 MAPK is known to trigger p53-dependent apoptosis. However, since almost all incidences of SCC exhibit UVB-induced mutations in the p53 gene, it is important to determine how p38 MAPK regulates oxidative stress in the mutant p53 environment. Our preliminary data show that the specific inhibition of p38 MAPK results in accelerated SCC growth in UVB-irradiated p53-/-/SKH-1 mice, increasing both the number and size of tumors. p38 MAPK inhibition was also associated with increased NADPH oxidase NOX2, a ROS-generating enzyme. In human SCC cells carrying mutant p53, both chemical and genetic inhibition of p38 MAPK leads to the upregulation of ROS and JNK/cyclin D1-mediated cell proliferation. The proposed study will explore the hypothesis that p38 MAPK regulates oxidative stress by blocking NOX2 in SCCs, and that p38 MAPK inhibition leads to the activation of JNK/cyclin D1 survival signaling. The proposed study will generate data related to the involvement of p38 MAPK and NOX signaling in the pathogenesis of UVB-induced SCCs, for which no detailed information is currently available. We anticipate that knowledge of oxidant signaling in human skin will provide crucial insights into the control of proliferation pathways during the pathogenesis of NMSCs.