Sec62 Protein Level is Crucial for the ER Stress Tolerance of Prostate Cancer
Sec62 Protein Level is Crucial for the ER Stress Tolerance of Prostate Cancer
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DOI：
10.1002/pros.21324
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发表时间：
2011-07-01
期刊：
影响因子：
2.8
通讯作者：
Wullich, Bernd
中科院分区：
文献类型：
--
作者：
Greiner, Markus;Kreutzer, Birgit;Wullich, Bernd
背景资料。我们此前曾报道，SEC62基因的过度表达是前列腺癌中普遍存在的现象。由于内质网(ER)应激诱导物质如thapsigargin在前列腺癌治疗中的应用在文献中被广泛讨论，我们调查了Sec62蛋白含量对这些药物对细胞反应的影响。方法：通过实时细胞分析和DU145细胞活力测试分析生长效应，DU145细胞是SEC62表达增加的细胞，PC3和LNCaP细胞与非肿瘤细胞相比SEC62表达相似。结果与PC3或LNCaP相比，thapsigargin处理DU145细胞后的细胞死亡倾向较低，siRNA介导的SEC62沉默导致thapsigargin处理的PC3细胞存活率降低，表明Sec62在细胞应激反应中发挥作用。细胞内[Ca~(2+)]的测定从分子水平证实了Sec62对thapsigargin细胞反应的影响。利用实时细胞分析，我们观察到在thapsigargin存在的情况下，LNCaP细胞雄激素刺激的丧失，以及Sec62耗竭对细胞生长的额外负面影响。此外，对于PC3和DU145细胞，在thapsigargin处理后，Sec62的缺失抑制了生长。结论：我们的数据表明Sec62在thapsigargin诱导的内质网应激反应中起着关键作用。当考虑使用thapsigargin类似物治疗时，这将在前列腺癌细胞中Sec62蛋白水平升高的背景下具有重要意义。前列腺癌71：1074-1083,2011。(C)2011年Wiley-Liss，Inc.
BACKGROUND. We previously reported that over-expression of the SEC62 gene is a widespread phenomenon in prostate cancer. Since the use of endoplasmic reticulum (ER) stress-inducing substances such as thapsigargin in prostate cancer therapy is widely discussed in the literature, we investigated the influence of Sec62 protein content on the cellular response to these drugs.METHODS. Growth effects were analyzed by real-time cell analysis and viability tests in DU145-cells representing an increased SEC62 expression or PC3- and LNCaP-cells representing a similar SEC62 expression compared to non-tumor cells. Ca2+-imaging in an established HeLa-system with fluorescent dye was used to study molecular effects of Sec62 depletion.RESULTS. We found a lower propensity toward apoptotic cell death after thapsigargin treatment for DU145 cells compared to PC3 or LNCaP and siRNA-mediated silencing of SEC62 resulted in a reduced viability of thapsigargin-treated PC3 cells, indicating that Sec62 functions in cellular stress response. Measurement of cytosolic [Ca2+] demonstrated the influence of Sec62 on the cellular response to thapsigargin on a molecular level. Using real-time cell analysis, we observed the loss of androgen stimulation of LNCaP cells in the presence of thapsigargin, and an additional negative effect on cell growth of Sec62 depletion. Also, for PC3- and DU145-cells Sec62 depletion inhibited growth after thapsigargin treatment.CONCLUSIONS. Our data indicate a crucial function of Sec62 in the response to thapsigargin-induced ER stress. This will be of great significance on the background of elevated Sec62 protein levels in prostate cancer cells when treatment with thapsigargin analogs is considered. Prostate 71: 1074-1083, 2011. (C) 2011 Wiley-Liss, Inc.