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Increase of ß_III- and ß_IVa-Tubulin Isotypes in Human Prostate Carcinoma Cells as a Result of Estramustine Resistance¹

Departments of Medicine and Pharmacology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111 [S. R., D. W. D., C. A. B., K. D. T., G. R. H.], and Thomas Jefferson University Hospital, Philadelphia, Pennsylvania 19107 [A. E. C.]

Estramustine (EM), an antimicrotubule agent, is effective against hormone-refractory prostate cancer when used in combination with vinblastine or paclitaxel. To understand the effect of EM on ß-tubulin, a cellular target for this class of drugs, human prostate carcinoma cells (DU-145) were made resistant to EM, and two cell lines were selected at 12- (EM-12) and 15-µM (EM-15) concentrations of the drug. These cell lines exhibited 8- to 9-fold resistance to EM and 2- to 4-fold cross-resistance to paclitaxel. Immunofluorescent staining of the cells with ß-tubulin isotype-specific antibodies showed a 6-fold increase in the ß_III-tubulin levels and moderate increase in overall ß-tubulin levels in EM-resistant cells when compared to DU-145 cells. This increase of ß_III isotype was confirmed by Western analysis. A reverse transcriptase-PCR assay was also employed using ß-tubulin isotype-specific primers to quantify ß-tubulin isotype RNA. A 4-fold increase in ß_III and a 3-fold increase in ß_IVa transcript were seen in both EM-resistant cell lines. These results indicate that overexpression of specific ß-tubulin isotypes may play a role in the cellular defense against EM and other antimicrotubule agents.

¹ This study was supported by an appropriation from the Commonwealth of Pennsylvania, CORE Grant NIH CA-06927, and Public Health Service Grant RO1 CA-57638 from the National Cancer Institute. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

² To whom requests for reprints should be addressed, at Department of Medicine, Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19111. Phone: (215) 728-2542; Fax: (215) 728-4333.

Received 12/ 7/95. Accepted 4/ 1/96.

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