Regulation of hypoxia and glycolysis through modulation of SIRT3 activity: SIRT3 activators for cancer metabolism and SIRT3 inhibitors for vascular disease
Pharmaceutical targeting of the SIRT3 activity may provide a novel therapeutic strategy for the treatment and/or prevention of cancer and vascular disease:
• SIRT 3 Activators for Solid tumors: The switch from oxidative to glycolytic metabolism is a hallmark of tumorigenesis. Cancer cells preferentially perform aerobic glycolysis as a means to rapidly synthesize biomass essential for their growth. This reprogramming is critical to cancer initiation and progression. As demonstrated by authors, SIRT3 has tumor suppressive function and acts by destabilizing HIF1? and reducing the glycolytic metabolism. A small molecule, protein or gene therapeutic that upregulates SIRT3 would reduce the level of glycolytic metabolism and deprive solid tumors of energy, without significantly impacting healthy cells that rely mostly on the TCA cycle.
• SIRT3 Inhibitors for Stroke, myocardial infarction and peripheral vascular disease: These conditions are characterized by interruption of blood supply that leads to hypoxia and often cell death. Recovery of the damaged tissue takes a long time and, in most cases, is never complete. Inhibitors of SIRT3 could become a first-aid treatments for these conditions – downregulation of SIRT3 would increase glycolytic metabolism and allow cells in impacted tissues to survive longer, reducing the long-term tissue damage.
Innovations and Advantages
Glucose is a universal nutrient – almost any living cell generates energy by breaking it down. In cells, glucose is converted into two molecules of pyruvate, which are further metabolized in mitochondria by the TCA cycle and oxidative phosphorylation. This metabolic pathway provides the highest amount of energy, however it requires oxygen and is relatively slow. Sometimes oxygen is in short supply, for example, when the vascular system cannot deliver enough oxygen to satisfy needs of a rapidly contracting muscle.
Hypoxia is also a hallmark of aggressively growing tumors and vascular disease, such a stroke or myocardial infarction. Under hypoxic conditions, including these disease conditions, cells switch to glycolytic metabolism. This metabolic pathway does not require oxygen and enables fast conversion of pyruvate into lactic acid to provide energy.
While the fundamental mechanisms of these metabolic pathways have been described for decades, little is known about the regulation of the balance between oxidative and glycolytic metabolism. Mitochondrial metabolic enzymes are heavily acetylated, which hints that reversible deacetylation of mitochondrial enzymes could be involved in the regulation of metabolic reprogramming.
Regulation of cellular metabolism: Researchers in the Haigis laboratory discovered the first example of a mitochondrial-driven, reversible switch enabling cells to rapidly induce metabolic reprogramming. They found that SIRT3, a mitochondrial-localized member of the sirtuin family of NAD-dependent deacetylases which is known to regulate global mitochondrial acetylation, is a crucial regulator of the switch to aerobic glycolysis. This implies that SIRT3 can serve as an important therapeutic target that would enable switching between glycolytic and oxidative metabolism. Several lines of evidence prove the clinically relevant connection between SIRT3 and cellular metabolism:
• SIRT3-null cells demonstrate a shift towards glycolytic metabolism. SIRT3 knock-out (KO) murine embryonic fibroblasts (MEFs) have faster glucose uptake, lower levels of TCA intermediates, higher levels of lactate and proliferate significantly faster than WT MEFs. In addition, the effects of SIRT3 deletion are similar to changes in metabolism caused by hypoxia. Taken together, these data show that the loss of SIRT3 causes metabolic reprogramming and resembles the phenotype of a fast-growing solid tumor.
• SIRT3 destabilizes HIF1?, the primary driver of increased glycolysis. The investigators also conducted experiments to elucidate the molecular mechanism of the metabolic reprogramming. They demonstrate in MEFs that SIRT3 knock-out leads to stabilization of hypoxia-inducible transcription factor (HIF1?), in a manner similar to TCA cycle defects.
• Tumor suppressive function of SIRT3 is confirmed in vivo. Transformed SIRT3 WT and KO MEFs were infected into nude mice. Tumors formed from 64% of KO injections but only 27% of WT injections. In addition, tumors lacking SIRT3 grew faster and larger than in control experiments. These in vivo data show that SIRT3 loss promotes glucose uptake and provides a growth advantage for tumor cells.
Intellectual Property Status: Patent(s) pending
This technology is available for worldwide, exclusive licensing and/or a collaborative research program with the Haigis laboratory.
Haigis, Marcia C.
For further information, please contact:
Michal Preminger, Director of Business Development
Reference Harvard Case #3785