Inhibition of soluble adenylyl cyclase increases the radiosensitivity of prostate cancer cells
Inhibition of soluble adenylyl cyclase increases the radiosensitivity of prostate cancer cells
复制标题
DOI：
10.1016/j.bbadis.2014.09.008
复制
发表时间：
2014-12-01
影响因子：
6.2
通讯作者：
Ladilov, Yury
中科院分区：
文献类型：
--
作者：
Appukuttan, Avinash;Flacke, Jan-Paul;Ladilov, Yury
肿瘤放射敏感性的药物调节是提高放射治疗效果的一个有前途的策略。CAMP信号传导在调节不同细胞类型（包括癌细胞）的增殖和凋亡中起重要作用。到目前为止，该途径的调节仅限于跨膜类腺苷酸环化酶。在本研究中，cAMP的替代来源，细胞内定位的可溶性腺苷酸环化酶（sAC），在前列腺癌细胞的放射敏感性的作用进行了研究。药理学抑制sAC活性导致显着抑制增殖，乳酸脱氢酶释放，诱导细胞凋亡。电离辐射与照射后立即部分抑制sAC活性（类似于50%）的组合协同抑制增殖并诱导凋亡。在正常前列腺上皮PNT 2细胞中过表达sAC增加cAMP含量，并在对照条件下加速细胞增殖。与对照细胞相比，在转化的PNT 2细胞中辐射的影响显著降低。对sAC诱导的辐射抗性的潜在细胞机制的分析揭示了B-Raf/ERK 1/2信号通路的sAC依赖性激活。与这一发现相一致，抑制前列腺癌细胞中的ERK 1/2增强了辐射的细胞毒性作用。总之，本研究表明，sAC依赖性信号在前列腺癌细胞的放射抗性中起着重要作用。这篇文章是题为：可溶性腺苷酸环化酶在健康和疾病中的作用特刊的一部分。(C)© 2014 Elsevier B. V.保留所有权利。
Pharmacological modulation of tumor radiosensitivity is a promising strategy for enhancing the outcome of radiotherapy. CAMP signaling plays an essential role in modulating the proliferation and apoptosis of different cell types, including cancer cells. Until now, the regulation of this pathway was restricted to the transmembrane class of adenylyl cyclases. In the present study, the role of an alternative source of cAMP, the intracellular localized soluble adenylyl cyclase (sAC), in the radiosensitivity of prostate cancer cells was investigated. Pharmacological inhibition of sAC activity led to marked suppression of proliferation, lactate dehydrogenase release, and induction of apoptosis. The combination of ionizing radiation with partial suppression of sAC activity (similar to 50%) immediately after irradiation synergistically inhibited proliferation and induced apoptosis. Overexpression of sAC in normal prostate epithelial PNT2 cells increased the cAMP content and accelerated cell proliferation under control conditions. The effects of radiation were significantly reduced in transformed PNT2 cells compared with control cells. Analysis of the underlying cellular mechanisms of sAC-induced radioresistance revealed the sAC-dependent activation of B-Raf/ERK1/2 signaling. In agreement with this finding, inhibition of ERK1/2 in prostate cancer cells enhanced the cytotoxic effect of irradiation. In conclusion, the present study suggests that sAC-dependent signaling plays an important role in the radioresistance of prostate cancer cells. This article is part of a Special Issue entitled: The role of soluble adenylyl cyclase in health and disease. (C) 2014 Elsevier B.V. All rights reserved.