Synthetic small interfering RNA targeting heat shock protein 105 induces apoptosis of various cancer cells both in vitro and in vivo
Synthetic small interfering RNA targeting heat shock protein 105 induces apoptosis of various cancer cells both in vitro and in vivo
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DOI：
10.1111/j.1349-7006.2006.00217.x
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发表时间：
2006-07-01
期刊：
影响因子：
5.7
通讯作者：
Nishimura, Yasuharu
中科院分区：
文献类型：
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作者：
Hosaka, Seiji;Nakatsura, Tetsuya;Nishimura, Yasuharu
我们以前报道过热休克蛋白105(HSP105)，它是通过用胰腺癌患者血清对重组cDNA表达文库(SEREX)的血清学分析而鉴定的，通过免疫组织化学分析在各种人类肿瘤和成年男性的睾丸中过表达。在本研究中，为了阐明HSP105蛋白在癌细胞中的生物学功能，我们首先建立了高表达小鼠HSP105的NIH3T3细胞(NIH3T3-HSP105)。NIH3T3-HSP105细胞对热休克或阿霉素诱导的细胞凋亡具有抵抗力。小干扰RNA(SiRNA)介导的抑制HSP105蛋白表达诱导了人癌细胞的凋亡，但不诱导成纤维细胞的凋亡。通过siRNA导入和阿霉素或热休克处理的组合，协同诱导了人结肠癌细胞系HCT116的凋亡。在体内，将siRNA接种到NOD SCID小鼠侧翼建立的人胃癌细胞系Kato-3中，抑制了肿瘤的生长。在HCT116细胞中，尽管HSP105蛋白与野生型P53蛋白结合，但这种siRNA诱导的细胞凋亡是通过caspase介导的，而不是P53抑癌蛋白。这些发现表明，HSP105在癌细胞中的结构性过表达通过保护肿瘤细胞免受凋亡而参与了恶性转化。因此，HSP105可能是一种新的肿瘤治疗靶分子，利用人工合成的siRNA抑制HSP105蛋白表达的治疗方案可能为肿瘤治疗提供新的策略。
We previously reported that heat shock protein 105 (HSP105), identified by serological analysis of a recombinant cDNA expression library (SEREX) using serum from a pancreatic cancer patient, was overexpressed in various human tumors and in the testis of adult men by immunohistochemical analysis. In the present study, to elucidate the biological function of the HSP105 protein in cancer cells, we first established NIH3T3 cells overexpressing murine HSP105 (NIH3T3-HSP105). The NIH3T3-HSP105 cells acquired resistance to apoptosis induced by heat shock or doxorubicin. The small interfering RNA (siRNA)-mediated suppression of HSP105 protein expression induced apoptosis in human cancer cells but not in fibroblasts. By a combination of siRNA introduction and doxorubicin or heat shock treatment, apoptosis was induced synergistically in a human colon cancer cell line, HCT116. In vivo, siRNA inoculation into the human gastric cancer cell line KATO-3 established in the flank of an NOD SCID mouse suppressed the tumor growth. This siRNA-induced apoptosis was mediated through caspases, but not the p53 tumor suppressor protein, even though the HSP105 protein was bound to wild-type p53 protein in HCT116 cells. These findings suggest that the constitutive overexpression of HSP105 in cancer cells is involved in malignant transformation by protecting tumor cells from apoptosis. HSP105 may thus be a novel target molecule for cancer therapy and a treatment regimen using synthetic siRNA to suppress the expression of HSP105 protein may provide a new strategy for cancer therapy.