Mechanism of paclitaxel resistance in a human prostate cancer cell line, PC3-PR, and its sensitization by cabazitaxel
Mechanism of paclitaxel resistance in a human prostate cancer cell line, PC3-PR, and its sensitization by cabazitaxel
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DOI：
10.1016/j.bbrc.2016.09.128
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发表时间：
2016-10-28
影响因子：
3.1
通讯作者：
Murate, Takashi
中科院分区：
文献类型：
--
作者：
Sobue, Sayaka;Mizutani, Naoki;Murate, Takashi
紫杉醇（PTX）是一种微管靶向药物，广泛用于治疗各种癌症。然而，在一系列治疗后可能会出现耐药性，这会严重影响患者的预后。我们利用人前列腺癌细胞系PC 3及其PTX耐药亚系PC 3-PR分析了FIX耐药的机制。与PC 3相比，PC 3-PR表现出一些可能与PTX耐药相关的独特表型，包括乙酰化α-微管蛋白和细胞周期调节因子p21表达减少，β III微管蛋白、组蛋白去乙酰化酶6（HDAC 6）表达增加，和抗凋亡蛋白Bcl 2。MDR 1和MRP 1与PTX耐药无关。虽然卡巴他赛（CDC），一种新的紫杉烷，已报告克服PTX耐药性，其作用机制是未知的。我们发现，用CTX处理PC 3-PR细胞诱导乙酰化α-微管蛋白和p21的表达，但不诱导相关调节因子p27、p15和p16或Bcl 2家族蛋白的表达。泛HDAC抑制剂曲马斯他汀A和辛二酰异羟肟酸以及HDAC 6特异性抑制剂微管蛋白抑制PC 3-PR增殖，并以与CTX类似的方式增加p21和乙酰化α-微管蛋白的表达。我们的数据揭示了对PTX和CDC的细胞反应。(C)2016 Elsevier Inc. All rights reserved.
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 FIX 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 alpha-tubulin and the cell cycle regulator p21, and increased expression of beta III 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 (CDC), 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 alpha-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 alpha-tubulin in a manner similar to CTX. Our data shed light on the cellular response to PTX and CDC. (C) 2016 Elsevier Inc. All rights reserved.