Professor, Department of Cell Biology
Adjunct Professor, Department of Obstetrics and Gynecology
B.S. cum laude Zoology, Duke University, Durham, North Carolina
Ph.D. Oncology, McArdle Laboratory for Cancer Research
The American Association for Cancer Research
Women in Cancer Research
American Association for the Advancement of Science
Sensitizing Tumors to Chemotherapy: Inhibition of Gamma Glutamyl Transpeptidase
Many tumors respond initially to chemotherapy but with continued treatment become resistant to the drugs. One of the most common mechanisms by which tumors develop resistance to chemotherapy is by inactivating the drugs with glutathione. We have shown that expression of the enzyme gamma-glutamyl transpeptidase (GGT) on the surface of the tumor cell enables the tumors to use extracellular glutathione as a source of cysteine. During treatment with chemotherapy the intracellular levels of glutathione are depleted and the intracellular concentration of cysteine can become rate-limiting for glutathione synthesis. Tumor cells that express GGT are resistant to chemotherapy drugs such cisplatin. We are developing inhibitors of GGT that can be used clinically to block GGT-mediated drug resistance. We identified a novel inhibitor of GGT that is the first uncompetitive inhibitor of GGT ever reported (JBC 284:9059, 2009). We continue to develop inhibitors of GGT that can be used in the clinic.
Tumors that are detected at an early stage are most responsive to treatment and in some cases can be cured surgically. However, for many of the most deadly cancers including liver, pancreatic and kidney cancer there are no routine screening tests that can be used to detect the tumor at an early stage. We are developing biomarkers that can be detected in the blood or the urine. We are focusing on the differences in glycosylation between normal cells and tumor cells. We have recently completed an in-depth characterization of the N-glycans on GGT expressed in normal human kidney and liver (JBC, 2010). We are now analyzing the glycans on GGT from tumor cells to identify glycopeptides that can be used as biomarkers for early detection of these often fatal tumors.
The Gamma-Glutamyl Transpeptidase Family of Enzymes
Many years of research on our laboratory and others have revealed the importance of gamma-glutamyl transpeptidase (GGT) in tumor development and drug resistance. GGT is only one of a family of enzymes encoded by the human genome. Three of the enzymes in this family have never been isolated and analyzed for enzyme activity. A fourth has only been studied in mice. We are expressing these enzymes and evaluating their ability to cleave gamma-glutamyl bonds with a novel assay that we have developed. These enzymes may have critical roles in cancer and in the many other diseases that involve glutathione and glutathione-conjugates.
Cooper, A.J.L., and Hanigan, M.H. (2010) Enzymes Involved in Processing of Glutathione Conjugates. In: Comprehensive Toxicology: Volume 4. Biotransformations, 2nd Edition. C. A. McQueen (Series Ed), F. P. Guengerich (Volume Ed), Elsevier Press, Oxford, Chapter 17 pp. 323-366.
West, M.B., Segu, Z.M., Feasley, C.L., Kang, P., Klouckova, I., Li, C., Novotny, M.V., West, C.M., Mechref, Y., and Hanigan, M.H. (2010) Analysis of Site-Specific Glycosylation of Renal and Hepatic γ- Glutamyl Transpeptidase from Normal Human Tissue. J. Biol. Chem., 285(38):29511-24.
West MB, Hanigan MH. (2010) γ-Glutamyl transpeptidase is a Heavily N-Glycosylated Heterodimer in HepG2 Cells. Arch Biochem Biophys. 504(2):177-81.
Hanigan, M.H., dela Cruz, B.L., Shord, S.S., Medina, P.J., Fazili, J. and Thompson, D.M. (2010) Optimizing Chemotherapy: Concomitant Medication Lists Clinical Pharmacology and Therapeutics 89:114-119.
Wickham, S., West, M.B., Cook, P.F, and Hanigan, M.H. (2011) Gamma-Glutamyl Compounds: Substrate Specificity of Gamma-Glutamyl Transpeptidase Enzymes. Analytical Biochemistry, 414:208-214.
West, M.B., Wickham, S., Quinalty, L.M., Pavlovicz, R.E., Li, C. and Hanigan. M.H. (2011) Autocatalytic Cleavage of Human g-Glutamyl transpeptidase Is Highly Dependent on N-Glycosylation at Asparagine 95 J. Biol. Chem., 286 (33):28876-88.
Wickham, S., Regan, N., West, M.B., Kumar, V.P., Thai, J., Li, P-K, Cook, P.F., Hanigan, M.H. (2011) Divergent Effects of Compounds on the Hydrolysis and Transpeptidation Reactions of Gamma-Glutamyl Transpeptidase. Enzyme Inhibition and Medicinal Chemistry 2011 Aug 24. pp1-14 [Epub ahead of print].
Cooper. A.J.L. and Hanigan, M.H. (2011) Letter to the Editor Food and Chemical Toxicology, 2011 Sep 10. [Epub ahead of print].
University of Oklahoma Health Sciences Center
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