Heat shock proteins play a crucial role in tumor-specific apoptosis by REIC/Dkk-3.
Heat shock proteins play a crucial role in tumor-specific apoptosis by REIC/Dkk-3.
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DOI：
10.3892/ijmm.20.1.37
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发表时间：
2007-07
影响因子：
5.4
通讯作者：
F. Abarzúa;M. Sakaguchi;R. Tanimoto;Hiroyuki Sonegawa;Dai Li;K. Edamura;Tomoko Kobayashi;Masami Watanabe;Y. Kashiwakura;H. Kaku;T. Saika;K. Nakamura;Y. Nasu;H. Kumon;N. Huh
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文献类型：
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作者：
F. Abarzúa;M. Sakaguchi;R. Tanimoto;Hiroyuki Sonegawa;Dai Li;K. Edamura;Tomoko Kobayashi;Masami Watanabe;Y. Kashiwakura;H. Kaku;T. Saika;K. Nakamura;Y. Nasu;H. Kumon;N. Huh
我们最近发现，REIC/Dickkopf-3（Dkk-3），一种肿瘤抑制基因的过表达，诱导凋亡的肿瘤细胞特异性的方式。本研究的目的是确定选择性诱导细胞凋亡的机制。首先，我们发现小鼠肾癌细胞系RENCA对携带REIC/Dkk-3的腺病毒（Ad-REIC）极其敏感，并且我们表明c-Jun N-末端激酶（JNK）的激活是细胞死亡的关键步骤，即与我们先前研究中观察到的人类前列腺癌和睾丸癌相似的过程。在干扰JNK激活的蛋白质中，热休克蛋白（Hsp）70/72在RENCA细胞中的表达较NIH 3 T3细胞中的表达降低。Hsp 70/72诱导剂保护RENCA细胞免受Ad-REIC诱导的凋亡，而Hsp 70/72抑制剂则使NIH 3 T3细胞对凋亡诱导敏感。这些结果表明，功能活跃的Hsp 70/72是肿瘤细胞特异性诱导凋亡细胞死亡的关键因素，Hsp 70/72的表达水平的分析可能是必不可少的，在确定的意义Ad-REIC为基础的基因治疗对人类癌症。
We recently showed that overexpression of REIC/Dickkopf-3 (Dkk-3), a tumor suppressor gene, induced apoptosis in a tumor cell-specific manner. The aim of the present study was to determine the mechanisms underlying the selective induction of apoptosis. At first, we found a mouse renal carcinoma cell line, RENCA, to be extremely sensitive to an adenovirus carrying REIC/Dkk-3 (Ad-REIC), and we showed that activation of c-Jun N-terminal kinase (JNK) was a critical step in cell death, i.e. a process similar to that in human prostate and testicular cancer observed in our previous studies. Among the proteins interfering with the activation of JNK, heat shock protein (Hsp)70/72 was reduced in expression in RENCA cells compared with that in NIH3T3 cells. An Hsp70/72 inducer protected RENCA cells from Ad-REIC-induced apoptosis, while an Hsp70/72 inhibitor sensitized NIH3T3 cells for apoptosis induction. These results indicate that functionally active Hsp70/72 is a key factor in tumor cell-specific induction of apoptotic cell death and that analyses of the expression levels of Hsp70/72 may be essential in determining the significance of Ad-REIC-based gene therapy against human cancer.