Harada H, Kizaka-Kondoh S, Li G, Itasaka S, Shibuya K, Inoue M, Hiraoka M
Department of Radiation Oncology and Image-Applied Therapy, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Oncogene. 2007 Nov 29;26(54):7508-16. doi: 10.1038/sj.onc.1210556. Epub 2007 Jun 11.
Human solid tumors contain hypoxic regions that have considerably lower oxygen tension than the normal tissues. Hypoxia offers resistance to radiotherapy and anticancer chemotherapy, as well as predispose to increased tumor metastases. Furthermore, hypoxia induces hypoxia-inducible factor-1 (HIF-1), which in turn increases tumor angiogenesis. Thus, eradication of HIF-1-active/hypoxic tumor cells is very important for cancer therapy. We have previously reported that procaspase-3 fused with a von Hippel-Lindau (VHL)-mediated protein destruction motif of alpha subunit of HIF-1 (HIF-1alpha) containing Pro564, named TAT-ODD-procaspase-3 (TOP3), specifically induced cell death to hypoxic cells in vivo as well as in vitro. We now report that TOP3 also eradicates the radiation-induced HIF-1-active tumor cells. HIF-1 activity in the xenografts of human tumor cells, which express luciferase under the transcriptional control of HIF-1, were monitored and quantified daily with an in vivo bioluminescence photon-counting device. HIF-1 activity in tumors was more rapidly increased by ionizing radiation (IR) compared to untreated tumors. TOP3 efficiently decreased the HIF-1-activity in irradiated tumors as well as unirradiated ones, indicating TOP3 eradicated tumor cells with HIF-1-activity induced by IR as well as hypoxia. Eradication of HIF-1-active/hypoxic cells in the xenografts during irradiation exhibited significant suppression in angiogenesis and strong enhancement in a long-term growth suppression of tumor xenografts. These results further strengthen the argument that HIF-1-active/hypoxic cells play crucial roles in angiogenesis and radioresistance.
人类实体瘤包含缺氧区域,这些区域的氧张力明显低于正常组织。缺氧会导致对放射治疗和抗癌化疗产生抗性,还会增加肿瘤转移的倾向。此外,缺氧会诱导缺氧诱导因子-1(HIF-1),进而增加肿瘤血管生成。因此,根除具有HIF-1活性/缺氧的肿瘤细胞对于癌症治疗非常重要。我们之前报道过,将原半胱天冬酶-3与含有Pro564的HIF-1α亚基的冯·希佩尔-林道(VHL)介导的蛋白质破坏基序融合,命名为TAT-ODD-原半胱天冬酶-3(TOP3),在体内和体外均能特异性地诱导缺氧细胞死亡。我们现在报道TOP3还能根除辐射诱导的具有HIF-1活性的肿瘤细胞。利用体内生物发光光子计数装置,每天监测并定量在HIF-1转录控制下表达荧光素酶的人肿瘤细胞异种移植瘤中的HIF-1活性。与未处理肿瘤相比,电离辐射(IR)使肿瘤中的HIF-1活性增加得更快。TOP3能有效降低照射肿瘤以及未照射肿瘤中的HIF-1活性,表明TOP3能根除由IR以及缺氧诱导的具有HIF-1活性的肿瘤细胞。在照射期间根除异种移植瘤中具有HIF-1活性/缺氧的细胞,在血管生成方面表现出显著抑制,并且在肿瘤异种移植瘤的长期生长抑制方面有强烈增强。这些结果进一步强化了这样的观点,即具有HIF-1活性/缺氧的细胞在血管生成和放射抗性中起关键作用。