Research Summary

Dr. Ayene’s laboratory investigates how molecular targeting can be used to increase the therapeutic response of cancer cells to gamma irradiation and chemotherapy. The major focus of his current research is to target functional cysteine molecules in various proteins that are involved in the survival of cancer cells. Dr. Ayene uses novel molecular and biochemical approaches to specifically target Ku70 to inhibit its expression or function, which causes an increased response of cancer cells to gamma irradiation and topoisomerase II inhibitors.

Ku is a heterodimer composed of the Ku70 and Ku86 proteins that is known to play an important role in V(D)J DNA recombination, apoptosis, telomere fusion and double strand break repair. The role of Ku in double strand break repair is relevant to cancer therapy as illustrated by the lack of Ku86 is one of the most etoposide and radiation responsive cell lines that have been studied (XRS5).

In addition to his major goal of sensitizing cancer cells to therapy, Dr Ayene is also interested in elucidating mechanisms of DNA repair, oncogene-mediated resistance to apoptosis, survival mechanisms of hypoxic cancer cells, and oxidative stress. He is presently the Principal Investigator of the NIH R01 grant “Oxidative Pentose Cycle in Hypoxic Cancer Cell Response” and also serves as a Co-Investigator for the NIH grants “Oxidative damage to DNA Repair Pathways” and “Redox Control of Radiation Response”.

Selected Publications

1. Tuttle SW, Maity, A, Oprysko PR, Kachur AV, Ayene IS, Biaglow JE, and Koch CJ: Detection of Reactive Oxygen Species via Endogenous Oxidative Pentose Phosphate Cycle Activity: Implications for HIF-1a Stability Under Moderate Hypoxia. J. Biol. Chem., in press. (Published online July 31, 2007).
2. Ayene IS, Biaglow JE, Kachur AV, Stamato TD and Koch CJ: Mutation in G6PD gene leads to loss of cellular control of protein glutathionylation: Mechanism and Implication. Journal of Cellular Biochemistry, In press (Published Online: 21 May 2007).
3. Ayene IS, Koch CJ and Krisch RE: DNA strand breakage by bivalent metal ions and ionizing radiation. International Journal of Radiation Biology, 83, 195-210, 2007.
4. Biaglow JE, Ayene IS, Tuttle SW, Koch CJ, Donahue J and Mieyal JJ: Role of Vicinal Protein Thiols in Radiation and Cytotoxic Responses. Radiat. Res. 165, 307–317, 2006.
5. Ayene IS, Ford LP and Koch CJ: Ku protein targeting by Ku70 small interfering RNA enhances human cancer cell response to topoisomerase II inhibitor and ϒ radiation. Mol. Cancer Ther. 4(4), 529-536, 2005.
6. Biaglow JE, Ayene IS, Koch CJ, Donahue J, Stamato TD, Mieyal JJ and Tuttle SW: Radiation response of cells during altered protein thiol redox. Radiat. Res., 159, 484-494, 2003.
7. Ayene IS, Stamato TD, Mauldin SK, Biaglow JE, Tuttle SW, Jenkins SF and Koch CJ: Mutation in the glucose-6-phosphate dehydrogenase gene leads to inactivation of Ku DNA end binding during oxidative stress. J. Biol. Chem., 277, 9929-9935, 2002.
8. Ayene IS, Koch CJ, Tuttle SW, Stamato T, Perez ML and Biaglow JE: Oxidation of cellular thiols by hydroxyethyldisulfide inhibits DNA double strand break rejoining in G6PD deficient mammalian cells. Int. J. Radiat. Biol. 76, 1523-1531, 2000.
9. Biaglow JE, Ayene IS, Koch CJ, Donahue J, Stamato T and Tuttle SW: G6PD deficient cells and the bioreduction of disulfides: Effects of DHEA, GSH depletion and phenylarsine oxide. Biochim. Biophys. Res. Comm. 273, 846-852, 2000.
10. Ayene IS, Bernhard EJ, Muschel RJ, McKenna WG, Krisch RE and Koch CJ: DNA as an important target in radiation induced apoptosis of myc and myc plus ras oncogene transfected cells. Int. J. Radiat. Biol., 76, 343-355, 2000.
11. Biaglow JE, Koch CJ, Tuttle S, Manevich Y, Ayene IS, Bernhard EJ, McKenna WG, and Kachur A: The measurement of bioreductive capacity of tumor cells using methylene blue. Int. J. Radiat. Oncol. Biol. Phys., 42, 769-773, 1998.
12. Zhao G, Ayene IS and Fisher AB: Role of iron in ischemia reperfusion oxidative injury of rat lungs. Am. J. Respir. Cell Mol. Biol. 16: 293-299, 1997.

Personnel

• Jie Li, M.D., Ph.D.
• DongLan Zhang

Graduate Student

• Kathleen Ward