Available Technology
Cancer Metabolism: SIRT4 as a Key Regulator of Glutamine Metabolism
Technology:
Target for cancer metabolism therapeutics
Markets Addressed
Cancer therapy: Activators of SIRT4 may be a novel, promising approach for modulating cancer metabolism, since many tumors require glutamine for an energy source and for survival. Tumors, with their increased energy demand and dysregulated metabolism, may be especially susceptible to inhibition of glutamine metabolism, leading to tumor death with minimal effects on nearby normal tissues.
Innovations and Advantages
Background - Cancer Metabolism: In many cancer cells, glutamine is the primary mitochondrial substrate and is required for maintenance of mitochondrial function and integrity. Glutamine is an essential metabolite for proliferating cells. Cancer cells show high levels of glutamine metabolism and glutamine is required for oncogenic activation. Some tumor cells, such as those with enhanced expression of the c-Myc oncogene, can not survive in the absence of glutamine. Methods for modulating the level of glutamine metabolism in a cell therefore offer great promise for the prevention and/or treatment of cancer.
Background - SIRT4: SIRT4 is a mitochondrial-localized member of the sirtuin family of NAD-dependent deacetylases. SIRT4 represses glutamate dehydrogenase (GDH) through ADP-ribosylation and deacetylation. GDH is an enzyme which converts glutamate to alpha-ketoglutarate, which then enters the tricarboxylic acid cycle (TCA) to produce energy.
SIRT4 is a Key Regulator of Glutamine Metabolism: Dr. Haigis’ laboratory has shown that SIRT4 represses, and is a key regulator of, glutamine metabolism. Cells treated with DNA damaging agents (DNA synthesis inhibitors; UV light) have significantly reduced glutamine consumption and NH4+ production, as well as significantly increased expression of SIRT4 and SIRT4 protein (and not SIRT1, SIRT3 or SIRT5). Using SIRT4 knock out cells, and cells that overexpress SIRT4, the lab further showed that SIRT4 is required for the repression of glutamine metabolism in response this genotoxic stress.
SIRT4 inhibits tumorigenesis: In vitro data demonstrate that SIRT4 knockout cells, but not SIRT4 wild-type cells, acquire a tumorigenic phenotype. They further show that glutamine metabolism is essential for the transformative properties of these cells. In vivo studies demonstrate that SIRT4 knockout mice have substantially increased tumor incidence, and in particular lung tumors. Ongoing studies in the lab are focused on the role of SIRT4 in tumorigenesis, and identifying the targets of SIRT4 implicated in glutamine metabolism and DNA damage.
Additional Information
Tweet
Inventor(s):
Haigis, Marcia C.
Jeong, Seungmin
Categories:
For further information, please contact:
Michal Preminger, Director of Business Development
(617) 432-0920
Reference Harvard Case #4188