HIGH EXPRESSION OF ACETYL-TUBULIN AS A CHEMORESISTANT BIOMARKER IN HUMAN DOCETAXEL-RESISTANCE PROSTATE CANCER CELLS

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Abstract

Background

Docetaxel-based chemotherapy has generally been considered as one of the effective treatments for prostate cancer. Unfortunately, clinical treatment with docetaxel often encounters a number of undesirable side-effects, including drug resistance. Therefore, it has become essential to identify molecular events that may be associated with the development of docetaxel resistance. Tubulin isoforms have been previously examined for their resistant ability to docetaxel in many cancers, but their real mechanisms remained unclear. In this study, we evaluated the feasibility of employing docetaxel as a cytotoxic agent for PC3 cells and to examine the role of acetyl-tubulin in docetaxel-resistant prostate cancer.

Methods

A series of docetaxel-resistant PC3/DX cell subclones was established by chronically exposing PC3 to progressively increased concentrations of docetaxel. Herein, we characterized the docetaxel-mediated cytoxicity and molecular events in PC3 and PC3/DX cells by the MTT assay, western blotting, RT–PCR and real-time PCR.

Results

Our results showed that levels of acetyl-tubulin, α-tubulin, β-tubulin, γ-tubulin and βIII-tubulin were significantly higher expression in PC3/DX than in parental PC3 cells by western blotting analysis. PC/DX with greater resistance to docetaxel had higher levels of acetyl-tubulin than in PC3 cells. The expression of acetyl-tubulin was gradually increased by docetaxel in a dose- and time-dependent manner in PC3 cells. Histone deacetylase 6, a deacetyl enzyme of tubulin, mRNA and protein levels were significantly decreased in PC3/DX than in PC3 cells. Interestingly, we also found an evident up-regulation of acetyl-tubulin protein expression after recombinant epidermal growth factor treatment in a time-dependent manner in PC3 cells.

Conclusions

Up-regulation of acetyl-tubulin may play an important chemoresistant role in docetaxel-resistant prostate cancer.

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