Mechanism of paclitaxel resistance in a human prostate cancer cell line, PC3-PR, and its sensitization by cabazitaxel
- College of Life and Health Sciences, Chubu University, Kasugai (Japan)
- Division of Molecular Carcinogenesis, Nagoya University Graduate School of Medicine, Nagoya (Japan)
- Tokai Gakuin University, Kakamigahara (Japan)
Paclitaxel (PTX) is a microtubule-targeting drug widely used for the treatment of a variety of cancers. However, drug resistance can emerge after a series of treatments, and this can seriously affect the patient's prognosis. Here, we analyzed the mechanism of PTX resistance using a human prostate cancer cell line, PC3, and its PTX-resistant subline, PC3-PR. Compared with PC3, PC3-PR exhibited some unique phenotypes that might be associated with PTX resistance, including decreased expression of acetylated α-tubulin and the cell cycle regulator p21, and increased expression of βIII tubulin, histone deacetylase 6 (HDAC6), and the anti-apoptotic protein Bcl2. The drug exporters MDR1 and MRP1 were not involved in PTX resistance. Although cabazitaxel (CTX), a novel taxoid, has been reported to overcome PTX resistance, its mechanism of action is unknown. We found that treatment of PC3-PR cells with CTX induced expression of acetylated α-tubulin and p21, but not the related regulators p27, p15, and p16 or the Bcl2 family proteins. The pan-HDAC inhibitors trichostatin A and suberanilohydroxamic acid and the HDAC6-specific inhibitor tubacin inhibited PC3-PR proliferation and increased expression of p21 and acetylated α-tubulin in a manner similar to CTX. Our data shed light on the cellular response to PTX and CTX. - Highlights: • PC3-PR but not PC3 cells are resistant with paclitaxel (PTX). • PTX-resistance of PC3-PR was not due to MDR1 and MRP1 overexpression. • PTX could not induce p21 and acetylated α tubulin expression of PC3-PR cells. • Cabazitaxel and HDAC inhibitor induced p21 and acetylated α-tubulin of PC3-PR. • Cabazitaxel and HDAC inhibitor equally suppressed PC3-PR cell growth.
- OSTI ID:
- 22696667
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 479, Issue 4; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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