Tumor cells reprogram their cell metabolism to sustain the increased metabolic demands of cell proliferation. The division of a tumor cell into two daughter cells involves the de novo synthesis of lipids, proteins, and nucleotides as well as ATP and NADPH. Historically, much attention has focused on glycolysis as the central metabolic pathway important for tumor cell metabolism. In the past few years, we have provided genetic and pharmacologic evidence that mitochondrial metabolism in addition to glucose metabolism is necessary for cancer cell proliferation and tumorigenesis. Mitochondrial metabolism serves three distinct functions that are critical for cancer cell proliferation and survival. First, the mitochondria generate the majority of ATP (bioenergetic) in most cancer cells. Second, mitochondrial tricarboxylic acid (TCA) cycle intermediates are precursors for the biosynthesis of macromolecules such as lipids and nucleotides. Third, the mitochondria generate high levels of reactive oxygen species (ROS) to activate proximal pro-tumorigenic signaling pathways through unidentified mechanisms. To compensate for the higher rate of ROS production, cancer cells have evolved adaptive mechanisms to increase the antioxidant properties of the cells and thereby maintain the pools of reduced glutathione and thioredoxin. This permits cancer cells to use ROS to activate proximal signaling pathways that stimulate neoplastic cell behavior, while simultaneously repairing the collateral oxidative damage caused by ROS in bystander macromolecules that would otherwise induce cancer cell death or senescence. Recently, we demonstrated that the biguanide metformin, a widely used anti-diabetic drug, reduces the tumor growth of human cancer cells in nude mice by inhibiting mitochondrial complex I through not fully understood mechanisms. Furthermore, mitochondrial targeted antioxidants can also reduce tumor growth. The present grant will elucidate the underlying mechanisms by which mitochondrial metabolism and ROS is essential for tumor growth and metastasis.

Public Health Relevance

The present grant will identify the mechanisms by which mitochondria are essential for tumorigenesis. Positive findings will elucidate new anti-cancer targets within mitochondria or dependent on mitochondrial metabolism.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
5R35CA197532-02
Application #
9211296
Study Section
Special Emphasis Panel (ZCA1-GRB-S (M1))
Program Officer
Espey, Michael G
Project Start
2016-06-01
Project End
2023-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
2
Fiscal Year
2017
Total Cost
$914,370
Indirect Cost
$314,370
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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