Mechanism of paclitaxel resistance in a human prostate cancer cell line, PC3-PR, and its sensitization by cabazitaxel.
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.
College of Life and Health Sciences, Chubu University, Kasugai, Japan.
Sayaka
S
Sobue
College of Life and Health Sciences, Chubu University, Kasugai, Japan.
Naoki
N
Mizutani
College of Life and Health Sciences, Chubu University, Kasugai, Japan.
Yuka
Y
Aoyama
College of Life and Health Sciences, Chubu University, Kasugai, Japan.
Yoshiyuki
Y
Kawamoto
Division of Molecular Carcinogenesis, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Motoshi
M
Suzuki
Tokai Gakuin University, Kakamigahara, Japan.
Yoshinori
Y
Nozawa
College of Life and Health Sciences, Chubu University, Kasugai, Japan.
Masatoshi
M
Ichihara
College of Life and Health Sciences, Chubu University, Kasugai, Japan. Electronic address: murate@isc.chubu.ac.jp.
Takashi
T
Murate
D000107:Acetylation; D000813:Anilides / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D017239:Paclitaxel / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D055550:Protein Stability / Q000187:drug effects; D043823:Taxoids / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology; D000077337:Vorinostat
D000813:Anilides; D000972:Antineoplastic Agents, Phytogenic; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D043823:Taxoids; D014404:Tubulin; D050257:Tubulin Modulators; C474316:tubacin; C012589:trichostatin A; C552428:cabazitaxel; D000077337:Vorinostat; D017239:Paclitaxel
Acetylated α-tubulin; Cabazitaxel; Cell growth inhibition; Human prostate cancer cell line; Paclitaxel resistance; p21