Inhibition of heme oxygenase-1 increases responsiveness of pancreatic cancer cells to anticancer treatment
Inhibition of heme oxygenase-1 increases responsiveness of pancreatic cancer cells to anticancer treatment
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DOI：
10.1158/1078-0432.ccr-04-2159
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发表时间：
2005-05-15
影响因子：
11.5
通讯作者：
Friess, H
中科院分区：
文献类型：
--
作者：
Berberat, PO;Dambrauskas, Z;Friess, H
血红素加氧酶-1（HO-1）被认为是保护细胞免受“应激”的关键酶。“它在不同类型的人类癌症中的过表达支持了HO-1提供生长优势并有助于细胞对化疗和放疗的抵抗的观点。鉴于胰腺癌患者的生存率很低，因为胰腺癌具有侵袭性生长行为，并且对所有已知形式的抗癌治疗具有特殊的耐药性，我们研究了HO-1在人胰腺癌细胞生长行为和预后中的表达。通过定量PCR、Western blot和共聚焦显微镜分析HO-1在人胰腺癌样品中的表达，并与正常胰腺进行比较。观察放、化疗对胰腺癌细胞HO-1表达的影响。此外，HO-1的表达被特异性抑制的小干扰RNA转染，随后的生长行为和抗癌治疗的抗性的改变进行了测试。胰腺癌组织HO-1 mRNA和蛋白表达水平分别是正常胰腺组织的6倍和3.5倍（P < 0.05）。癌组织中显示显着的HO-1免疫反应在肿瘤细胞和肿瘤相关的免疫细胞。用吉西他滨或放射治疗胰腺癌细胞系强烈诱导HO-1表达。HO-1表达的靶向敲低导致胰腺癌细胞的显著生长抑制，并使肿瘤细胞对放疗和化疗显着更敏感。因此，特异性抑制HO-1表达可能成为胰腺癌治疗的一个新选择，并可作为化疗和放疗的增敏剂。
Heme oxygenase-1 (HO-1) is believed to represent a key enzyme for the protection of cells against "stress." Its overexpression in different types of human cancers supports the notion that HO-1 provides a growth advantage and contributes to cellular resistance against chemotherapy and radiotherapy. Given the poor survival rates of patients with pancreatic cancer due to its aggressive growth behavior and its exceptional resistance to all known forms of anticancer treatment, we have investigated the expression of HO-1 in human pancreatic cancer cells growth behavior and prognosis. Expression of HO-1 was analyzed in human pancreatic cancer samples in comparison with normal pancreas by quantitative PCR, Western blot, and confocal microscopy. The influence of radiotherapy and chemotherapy on HO-1 expression in pancreatic cancer cell lines was evaluated. Furthermore, HO-1 expression was specifically suppressed by small interfering RNA transfection and subsequently the alterations of growth behavior and resistance to anticancer treatment were tested. Human pancreatic cancer showed a 6-fold and 3.5-fold HO-1 up-regulation in comparison to normal pancreas based on mRNA and protein level, respectively (P < 0.05). Cancer tissues revealed marked HO-1 immunoreactivity in tumor cells and in tumor associated immunocytes. Treatment of the pancreatic cancer cell lines with gemcitabine or radiation strongly induced HO-1 expression. Targeted knockdown of HO-1 expression led to pronounced growth inhibition of the pancreatic cancer cells and made tumor cells significantly more sensitive to radiotherapy and chemotherapy. Therefore, specific inhibition of HO-1 expression may be a new option in pancreatic cancer therapy and may be used as sensitizer to chemotherapy and radiotherapy.