Environment Dictates Dependence on Mitochondrial Complex I for NAD+ and Aspartate Production and Determines Cancer Cell Sensitivity to Metformin

• Published in: Cell metabolism 2016-11, Vol.24 (5), p.716-727
• Main Authors: Gui, Dan Y., Sullivan, Lucas B., Luengo, Alba, Hosios, Aaron M., Bush, Lauren N., Gitego, Nadege, Davidson, Shawn M., Freinkman, Elizaveta, Thomas, Craig J., Vander Heiden, Matthew G.
• Format: Article
• Language: English
• Subjects: Animals; aspartate; Aspartic Acid - biosynthesis; biguanide; cancer metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; complex I; drug sensitivity; Electron Transport Complex I - metabolism; Homeostasis - drug effects; Humans; metformin; Metformin - pharmacology; Mice, Nude; mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; NAD - metabolism; NAD+/NADH ratio; Neoplasms - pathology; Pyruvic Acid - pharmacology; Tumor Microenvironment - drug effects
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2016.09.006

Metformin use is associated with reduced cancer mortality, but how metformin impacts cancer outcomes is controversial. Although metformin can act on cells autonomously to inhibit tumor growth, the doses of metformin that inhibit proliferation in tissue culture are much higher than what has been described in vivo. Here, we show that the environment drastically alters sensitivity to metformin and other complex I inhibitors. We find that complex I supports proliferation by regenerating nicotinamide adenine dinucleotide (NAD)+, and metformin’s anti-proliferative effect is due to loss of NAD+/NADH homeostasis and inhibition of aspartate biosynthesis. However, complex I is only one of many inputs that determines the cellular NAD+/NADH ratio, and dependency on complex I is dictated by the activity of other pathways that affect NAD+ regeneration and aspartate levels. This suggests that cancer drug sensitivity and resistance are not intrinsic properties of cancer cells, and demonstrates that the environment can dictate sensitivity to therapies that impact cell metabolism. [Display omitted] •Metformin inhibits cell proliferation by decreasing the intracellular NAD+/NADH ratio•Metformin treatment in vivo leads to decreased tumor NAD+ and aspartate•The environment dictates cellular dependence on mitochondrial complex I•Drug sensitivity and resistance can be influenced by the environment Metformin use is associated with reduced cancer mortality. Gui et al. show that metformin reduces cell proliferation by decreasing the NAD+/NADH ratio and inhibiting aspartate production. Additionally, they show that the metabolic environment influences sensitivity to metformin, suggesting that drug sensitivity or resistance is not necessarily an intrinsic property of cancer cells.