Lung cancer is the most common cause of cancer-related death in both men and women in the United States. Eighty percent of lung cancers are non-small cell lung cancers (NSCLCs) and 30% of NSCLCs are adenocarcinomas, which include a rising population of cancer cases that occur in nonsmokers. Mutations in the Kras oncogene, which signals through a cascade of kinases to promote cellular proliferation, have been identified in 20-30% of NSCLCs. Therapeutic targeting of Kras-driven tumors necessitates the identification of signaling pathways required for oncogenic Kras-driven proliferation. Kras-driven lung cancer cells display higher levels of reactive oxygen species (ROS) than noncancerous lung cells. ROS have been proposed to serve as signaling molecules to activate numerous signaling pathways, including PI3K, ERK1/2 MAPK, and the transcription factors hypoxia inducible factors (HIFs), which promote tumor cell proliferation, angiogenesis, and metastasis. The major form of ROS that participates in signaling in the cytosol is hydrogen peroxide (H2O2), which is generated by its conversion from superoxide (O2-) by copper-zinc superoxide dismutase (SOD1) in the cytosol. We have reported that O2- from mitochondrial complex III and its conversion to H2O2 in the cytosol are required to initiate Kras-induced cellular proliferation and hypoxic activation of HIFs in tumor cells. Presently, it is not known whether complex III-generated O2- or H2O2-dependent signaling in the cytosol is required for oncogenic Kras-driven lung tumorigenicity in vivo. Recent studies indicate that glutamine is a major fuel for the TCA cycle to generate NADH and FADH2. These reducing equivalents donate electrons to the electron transport chain resulting in complex III generated superoxide. We recently reported that Kras-driven tumor cells also utilize glutamine to fuel the TCA cycle. Glutamine can be converted by glutaminase (GLS) to glutamate, which enters the TCA cycle through conversion into alpha-ketoglutarate by aminotransferases (GPT2 or GOT2) or glutamate dehydrogenase (GDH). Preliminary data indicate that preventing glutamine entry into the TCA cycle using inhibitors of aminotransferases or RNAi of GPT2 reduces anchorage-independent growth of oncogenic Kras-driven tumor cells. However, it is not known if inhibition of GPT2 would attenuate lung adenocarcinoma in vivo or if GPT2 is dispensable for normal tissues in the adult mouse. The major goal of this grant is to genetically determine whether diminishing complex III generated superoxide, production of cytosolic hydrogen peroxide, and glutamine utilization by the TCA cycle will attenuate tumorigenesis in the oncogenic Kras-driven mouse model of lung adenocarcinoma and in an orthotopic mouse model using human A549 lung adenocarcinoma cells harboring a Kras mutation.

Public Health Relevance

Lung cancer is the most common cause of cancer-related death in both men and women in the United States. The major goal is to determine whether preventing mitochondrial metabolism or production of hydrogen peroxide would be effective in diminishing lung cancer. Positive results would provide a rationale for therapies targeting metabolic enzymes that regulate mitochondrial metabolism.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Espey, Michael G
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Northwestern University at Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
DeBerardinis, Ralph J; Chandel, Navdeep S (2016) Fundamentals of cancer metabolism. Sci Adv 2:e1600200
Martínez-Reyes, Inmaculada; Diebold, Lauren P; Kong, Hyewon et al. (2016) TCA Cycle and Mitochondrial Membrane Potential Are Necessary for Diverse Biological Functions. Mol Cell 61:199-209
Weinberg, Samuel E; Chandel, Navdeep S (2015) Targeting mitochondria metabolism for cancer therapy. Nat Chem Biol 11:9-15
Weinberg, Samuel E; Sena, Laura A; Chandel, Navdeep S (2015) Mitochondria in the regulation of innate and adaptive immunity. Immunity 42:406-17
Chandel, Navdeep S (2015) Evolution of Mitochondria as Signaling Organelles. Cell Metab 22:204-6
Martínez-Reyes, Inmaculada; Chandel, Navdeep S (2014) Mitochondrial one-carbon metabolism maintains redox balance during hypoxia. Cancer Discov 4:1371-3
Schieber, Michael; Chandel, Navdeep S (2014) ROS function in redox signaling and oxidative stress. Curr Biol 24:R453-62
Glasauer, Andrea; Chandel, Navdeep S (2014) Targeting antioxidants for cancer therapy. Biochem Pharmacol 92:90-101
Wheaton, William W; Weinberg, Samuel E; Hamanaka, Robert B et al. (2014) Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. Elife 3:e02242
Chandel, Navdeep S (2014) Mitochondria as signaling organelles. BMC Biol 12:34

Showing the most recent 10 out of 36 publications