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Antiproliferative Effects of Src Inhibition on Medullary Thyroid Cancer

Departments of Surgery and Pulmonary Medicine (Z.L., J.F., X.Z., Y.G., G.A.S., T.A., F.E.N.), University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390; Dallas Veterans Affairs Medical Center (Z.L., Y.G., G.A.S., T.A., F.E.N.), Dallas, Texas 75216; and University of Arkansas for Medical Sciences (L.T.K.), Little Rock, Arkansas 72205

Address all correspondence and requests for reprints to: Fiemu E. Nwariaku M.D., Department of Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9156. E-mail: Fiemu.Nwariaku{at}UTSouthwestern.edu.

There is no effective treatment for recurrent or metastatic medullary thyroid cancer (MTC). Hereditary MTC is associated with mutations in the RET protooncogene, which encodes for a tyrosine kinase. We postulated that Src tyrosine kinases regulate MTC proliferation.

Proliferation of the human MTC cell line, TT, was examined in the presence of a Src-specific tyrosine kinase inhibitor, PP2, or genistein. Cell counts were performed with a Coulter counter or by flow cytometry. DNA synthesis was evaluated by bromodeoxyuridine incorporation. A cell death ELISA was used to assess apoptosis. Akt phosphorylation was determined by Western immunoblot. MAPK activity was measured using an immunoprecipitation kinase assay, and MAPK inhibition was achieved with SB202190 (p38 MAPK) and PD098059 (MAPK kinase). Data were analyzed by ANOVA.

Compared with controls, PP2 reduced DNA synthesis, abolished Akt phosphorylation, and increased apoptosis. The MAPK kinase inhibitor, PD098059, attenuated DNA synthesis, whereas genistein caused modest declines in cell count and DNA synthesis and minimal changes in apoptosis.

We conclude that Src-dependent MTC proliferation occurs via increased DNA synthesis and reduced apoptosis. The latter effect may be mediated by Akt survival signals. Modulation of Src activity is a potential therapeutic target in MTC.

This work was supported in part by a Robert Wood Johnson Minority Medical Faculty Development Award and the VA Merit Review Entry Program Grant.

Abbreviations: ATF, Activating transcription factor; BrdU, bromodeoxyuridine; MEK, MAPK kinase; MEN, multiple endocrine neoplasia; MTC, medullary thyroid cancer.

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