Paclitaxel resistance in cells with reduced beta-tubulin.
We previously described the isolation of colcemid resistant Chinese hamster ovary cell lines containing alpha- and beta-tubulin mutations that increase microtubule assembly and stability. By analyzing colcemid sensitive revertants from one of the beta-tubulin mutants, we now find that loss or inactivation of the mutant allele represents the most common mechanism of reversion. Consistent with this loss, the revertants have 35% less tubulin at steady state, no evidence for the presence of a mutant polypeptide, and a normal extent of tubulin polymerization. In addition to the loss of colcemid resistance, the revertant cells exhibit increased resistance to paclitaxel relative to wild-type cells. This paclitaxel resistance can be suppressed by transfecting the revertant cells with a cDNA for wild-type beta-tubulin, indicating that the reduction in tubulin in the revertant cells is responsible for the resistance phenotype. We propose that reducing tubulin levels may represent a novel mechanism of paclitaxel resistance.
Wang
Yaqing
Y
Department of Integrative Biology and Pharmacology, University of Texas Medical School, Houston, 77030, USA.
Cabral
Fernando
F
D000483:Alleles; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003703:Demecolcine / Q000494:pharmacology; D004351:Drug Resistance; D017353:Gene Deletion; D020128:Inhibitory Concentration 50; D008869:Microtubule-Associated Proteins / Q000032:analysis / Q000187:drug effects / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D014404:Tubulin / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; D008869:Microtubule-Associated Proteins; D014404:Tubulin; D017239:Paclitaxel; D003703:Demecolcine