Nitrogen Trapping as a Therapeutic Strategy in Tumors with Mitochondrial Dysfunction.

Abstract

Under conditions of inherent or induced mitochondrial dysfunction, cancer cells manifest overlapping metabolic phenotypes, suggesting that they may be targeted via a common approach. Here, we use multiple oxidative phosphorylation (OXPHOS)-competent and incompetent cancer cell pairs to demonstrate that treatment with α-ketoglutarate (aKG) esters elicits rapid death of OXPHOS-deficient cancer cells by elevating intracellular aKG concentrations, thereby sequestering nitrogen from aspartate through glutamic-oxaloacetic transaminase 1 (GOT1). Exhaustion of aspartate in these cells resulted in immediate depletion of adenylates, which plays a central role in mediating mTOR inactivation and inhibition of glycolysis. aKG esters also conferred cytotoxicity in a variety of cancer types if their cell respiration was obstructed by hypoxia or by chemical inhibition of the electron transport chain (ETC), both of which are known to increase aspartate and GOT1 dependencies. Furthermore, preclinical mouse studies suggested that cell-permeable aKG displays a good biosafety profile, eliminates aspartate only in OXPHOS-incompetent tumors, and prevents their growth and metastasis. This study reveals a novel cytotoxic mechanism for the metabolite aKG and identifies cell-permeable aKG, either by itself or in combination with ETC inhibitors, as a potential anticancer approach. SIGNIFICANCE: These findings demonstrate that OXPHOS deficiency caused by either hypoxia or mutations, which can significantly increase cancer virulence, renders tumors sensitive to aKG esters by targeting their dependence upon GOT1 for aspartate synthesis. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/17/3492/F1.large.jpg.

• Authors: Hanumantha Rao Madala, Iiro Taneli Helenius, Wen Zhou, Evanna Mills, Yiyun Zhang, Yan Liu, Ana M Metelo, Michelle L Kelley, Surendra Punganuru, Kyung Bo Kim, Benjamin Olenchock, Eugene Rhee, Andrew M Intlekofer, Othon Iliopoulos, Edward Chouchani, Jing-Ruey Joanna Yeh
• Journal: Cancer research (Cancer Res) Vol. 80 Issue 17 Pg. 3492-3506 (09 01 2020) ISSN: 1538-7445 [Electronic] United States
• PMID: 32651261 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• Ketoglutaric Acids
• Nitrogen

Topics

• Animals
• Cell Line, Tumor
• Humans
• Ketoglutaric Acids (pharmacology)
• Mice, Nude
• Mitochondrial Diseases (metabolism)
• Neoplasms (metabolism)
• Nitrogen (metabolism)
• Oxidative Phosphorylation (drug effects)
• Xenograft Model Antitumor Assays