Increased expression of the major heat shock protein Hsp72 in human prostate carcinoma cells is dispensable for their viability but confers resistance to a variety of anticancer agents
Increased expression of the major heat shock protein Hsp72 in human prostate carcinoma cells is dispensable for their viability but confers resistance to a variety of anticancer agents
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DOI：
10.1038/sj.onc.1208495
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发表时间：
2005-05-05
期刊：
影响因子：
8
通讯作者：
Sherman, MY
中科院分区：
文献类型：
--
作者：
Gabai, VL;Budagova, KR;Sherman, MY
主要的热休克蛋白Hsp 72在各种类型的癌症中以高水平表达。在这里，我们试图澄清热休克蛋白72在前列腺癌细胞中的作用，通过使用siRNA和反义RNA的方法研究这种蛋白质的特异性下调的影响。与以前的报道相反，特异性消耗Hsp 72不会降低前列腺癌细胞系PC-3和DU-145的活力。然而，即使是短期下调这些细胞中的热休克蛋白72使他们更敏感的高温，蛋白酶体和热休克蛋白90的抑制剂，和肿瘤坏死因子。有趣的是，PC-3细胞中Hsp 72的持续下调超过3周加重了这些作用，并增强了细胞对氧化应激、辐射、顺铂、长春碱和紫杉醇的敏感性。对抗癌剂的敏感性增加是由于细胞凋亡增加以及其他类型的细胞死亡，这导致克隆形成存活的丧失。Hsp 72的长期下调导致主要存活途径ERK和NF-κ B的严重抑制，这可能是前列腺癌细胞对各种抗癌治疗的敏感性增强的原因，以及细胞在软琼脂中形成集落的能力降低。
The major heat shock protein Hsp72 is expressed at high levels in various types of cancer. Here we attempt to clarify the role of Hsp72 in prostate cancer cells by studying the effects of specific downregulation of this protein using siRNA and antisense RNA approaches. Contrary to previous reports, specific depletion of Hsp72 did not reduce viability of the prostate carcinoma cell lines PC-3 and DU-145. However, even short-term downregulation of Hsp72 in these cells made them more sensitive to hyperthermia, inhibitors of proteasome and Hsp90, and tumor necrosis factor. Interestingly, prolonged downregulation of Hsp72 in PC-3 cells over 3 weeks aggravated these effects, as well as enhanced the sensitivity of cells to oxidative stress, radiation, cis-platinum, vinblastin and taxol. The increased sensitivity to the anticancer agents was due to increased apoptosis, as well as other types of cell death, which resulted in the loss of clonogenic survival. Prolonged downregulation of Hsp72 led to severe suppression of the major survival pathways, ERK and NF-kappa B, which may be responsible for enhanced sensitivity of prostate carcinoma cells to a variety of anticancer treatments, as well as reduction of the cell's capability of forming colonies in soft agar.