T 型钙通道驱动雄激素受体阴性前列腺癌细胞的增殖。
T-type calcium channels drive the proliferation of androgen-receptor negative prostate cancer cells.
机构信息
School of Life Health and Chemical Sciences, The Open University, Milton Keynes, UK.
Department of Biology, University of Pisa, Pisa, Italy.
出版信息
Prostate. 2019 Sep;79(13):1580-1586. doi: 10.1002/pros.23879. Epub 2019 Jul 23.
BACKGROUND
Androgen deprivation therapy (ADT) is the treatment of choice for metastatic prostate cancer (PCa). After an initial response to ADT, PCa cells can generate castration resistant (CRPC) or neuroendocrine (NEPC) malignancies, which are incurable. T-type calcium channels (TTCCs) are emerging as promising therapeutic targets for several cancers, but their role in PCa progression has never been investigated.
METHODS
To examine the role of TTCCs in PCa, we analyzed their expression level, copy number variants (CNV) and prognostic significance using clinical datasets (Oncomine and cBioPortal). We then evaluated TTCC expression in a panel of PCa cell lines and measured the effect of their inhibition on cell proliferation and survival using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and caspase assays.
RESULTS
TTCCs were upregulated in PCas harboring androgen receptor (AR) mutations; CNV rate was positively associated with PCa progression. Higher expression of one TTCC isoform (CACNA1G) predicted poorer postoperative prognosis in early stage PCa samples. Pharmacological or small interfering RNA (siRNA)-based inhibition of TTCCs caused a decrease in PC-3 cell survival and proliferation.
CONCLUSIONS
Our results show that TTCCs are overexpressed in advanced forms of PCa and correlate with a poorer prognosis. TTCC inhibition reduces cell proliferation and survival, suggesting that there may be possible value in the therapeutic targeting of TTCCs in advanced PCa.
背景
去势治疗（ADT）是转移性前列腺癌（PCa）的首选治疗方法。在 ADT 初始反应后，PCa 细胞可产生去势抵抗（CRPC）或神经内分泌（NEPC）恶性肿瘤，这些肿瘤无法治愈。T 型钙通道（TTCC）作为几种癌症的有前途的治疗靶点正在出现，但它们在 PCa 进展中的作用尚未被研究过。
方法
为了研究 TTCC 在 PCa 中的作用，我们使用临床数据集（Oncomine 和 cBioPortal）分析了它们的表达水平、拷贝数变异（CNV）和预后意义。然后，我们评估了 TTCC 在一系列 PCa 细胞系中的表达，并使用 3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四唑溴盐（MTT）和半胱天冬酶测定法测量了其抑制对细胞增殖和存活的影响。
结果
携带雄激素受体（AR）突变的 PCa 中 TTCC 上调；CNV 率与 PCa 进展呈正相关。一种 TTCC 同工型（CACNA1G）的高表达预测了早期 PCa 样本中较差的术后预后。TTCC 的药理学或小干扰 RNA（siRNA）抑制导致 PC-3 细胞存活和增殖减少。
结论
我们的结果表明，TTCC 在晚期 PCa 中过度表达，并与较差的预后相关。TTCC 抑制降低了细胞增殖和存活，这表明在晚期 PCa 中靶向 TTCC 可能具有一定的治疗价值。
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