Lung cancer is the leading cause of cancer related mortality in both men and women and remains a major health issue. More than 159,000 individuals will die from lung cancer in the coming year, more than breast, prostate and colon cancer combined. The majority of lung cancer cases is attributable to tobacco smoking and in some cases other environmental risk factors. Although the relative risk of developing lung cancer declines dramatically in smokers who quit, former smokers remain at risk for the disease. Several recent studies show that greater than 50% of newly diagnosed lung cancers occur in former smokers. Estimates suggest there are approximately equal numbers of smokers and former smokers in the United States. Since smoking cessation is a major public health initiative, former smokers will increasingly account for a higher percentage of lung cancer cases. Therefore, two high-risk population groups exist for lung cancer and improved disease management can be beneficial to both current and former smokers. Additionally, resistance to chemotherapy used in lung cancer treatment remains a major problem and a better understanding of the mechanisms for resistance could lead to therapies that are more effective. The MAP3K8 gene is a mitogen activated protein (MAP) kinase kinase kinase expressed in a variety of cells and found to be oncogenic and constitutively activated when altered at the 3'terminus. However, mutation of the gene is rare, but altered MAP3K8 expression is associated with multiple tumor types. MAP3K8 possesses the unique characteristic of activating multiple cascades, including both proliferative and apoptotic signal transduction pathways such as the MEK-1 and SEK-1 pathways, respectively. In NIH3T3 transfection assays utilizing lung tumor DNA, our lab identified a 3'alteration of MAP3K8 similar to the previous reports using rodent models. We first hypothesized that MAP3K8 might be a target for mutation since we were the first group to report an activating mutation in a primary human tumor. However, it has become clear that mutations are not a common event in tumorigenesis for this gene. Subsequently we showed varied levels of expression of the gene in lung tumor cell lines. This led us to investigate other downstream pathways to explain the tumorigenic potential of MAP3K8. These included transcription factor array analysis and protein kinase array experiments. We were able to confirm other reports in the literature demonstrating upregulation of NF-kappaB and AP-1 as well as identify other important transcription factors not reported in the literature. These and other experiments, as well as published reports lead us to hypothesize that increased expression of MAP3K8 occurs in lung cancer and contributes to disease progression. We have recently shown that increased protein expression of MAP3K8 in lung tumor cell lines leads to changes in downstream signaling pathways and ultimately transcription of important genes in cell survival. To test the effects of MAP3K8 over expression on survival in the presence of a commonly used chemotherapeutic, paclitaxel, we stably transfected a normal tracheal epithelial cell line with MAP3K8. These data suggest MAP3K8 expression is altered in lung cancer cells lines and because of its role in the inflammatory response and cell survival, MAP3K8 over expression may be involved in tumor progression. We have now demonstrated the importance of MAP3K8 expression levels in resistance to paclitaxel.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011108-06
Application #
8763347
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2013
Total Cost
$217,494
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
DeCicco-Skinner, Kathleen L; Nolan, Sabrina J; Deshpande, Monika M et al. (2013) Altered prostanoid signaling contributes to increased skin tumorigenesis in Tpl2 knockout mice. PLoS One 8:e56212