Lung cancer results in the largest number of cancer-related deaths in the United States. Non-small cell lung cancer (NSCLC) patient tumors overexpress NADPH oxidases that produce intracellular hydrogen peroxide (H2O2) and play an important role in lung cancer tumorigenicity. To date, our preliminary results demonstrate that NOX activity is functionally important for NCSLC transformation, escape from anoikis, phosphorylation signaling, and redox regulation of cysteines in several novel intracellular proteins. The fundamental goal of this proposal is to study the molecular details of NOX-dependent redox signaling in lung cancer biology.
Aim 1 of the proposal will characterize the functional role of NOX isoforms overexpressed in lung patient tumors in lung cancer tumorigenicity.
Aim 2 will examine the regulatory crosstalk between phosphorylation signaling and NOX activity by profiling NOX-dependent kinase activity.
Aim 3 will quantitatively map the cysteine targets of NOX- derived H2O2 in NSCLC upon NOX inhibition. Investigating the role of NOX enzymes and redox signaling in lung cancer will shed light on orthogonal control mechanisms regulating cancer cell growth, transformation and evasion of anoikis. There is a strong link between RAS mutations, overexpression of NOX and increased ROS production. Therefore, investigating redox signaling in NSCLC may identify new regulators and therapeutic targets for intervention in lung cancer, especially RAS-driven tumors with no clear therapeutic option.

Public Health Relevance

Lung cancer results in the largest number of cancer-related deaths in the United States with over 50% of non- small cell lung cancers overexpressing NADPH oxidases. The goal of this proposal is to investigate the role of NADPH oxidase enzymes and redox signaling in lung cancer biology and therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA200893-05
Application #
9964687
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Salnikow, Konstantin
Project Start
2016-07-01
Project End
2021-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130