Preferential cytotoxicity of bortezomib toward hypoxic tumor cells via overactivation of endoplasmic reticulum stress pathways.
Preferential cytotoxicity of bortezomib toward hypoxic tumor cells via overactivation of endoplasmic reticulum stress pathways.
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DOI：
10.1158/0008-5472.can-08-2873
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发表时间：
2008-11-15
期刊：
影响因子：
11.2
通讯作者：
Koumenis C
中科院分区：
文献类型：
--
作者：
Fels DR;Ye J;Segan AT;Kridel SJ;Spiotto M;Olson M;Koong AC;Koumenis C
缺氧是肿瘤微环境的动态特征，有助于耐药性和癌症进展。我们先前表明，内质网（ER）应激引起的未折叠蛋白反应（UPR）的成分也被缺氧在体外以及动物和人类患者肿瘤中激活。在这里，我们报告说，与常氧性肿瘤细胞相比，与常氧性肿瘤细胞相比，诸如Thapsigargin或临床使用的蛋白酶体抑制剂硼替佐米之类的ER应激源显示出明显更高的细胞毒性，并伴随着In Vivo中UPR效应子和UPR报告的活性增强。用翻译抑制剂环己酰亚胺治疗细胞的细胞可减轻ER负荷，改善这种增强的细胞毒性，表明细胞毒性升高是ER应力依赖性的。细胞死亡的模式取决于细胞类型，因为DLD1结直肠癌细胞表现出增强的细胞凋亡，而在HeLa宫颈癌细胞中，活化的自噬封闭了凋亡，并最终导致坏死。自噬的药理学或遗传消融增加了凋亡的水平。这些结果表明，通常对遗传毒性剂具有更耐药性的缺氧性肿瘤细胞对蛋白酶体抑制剂高度敏感，并表明将硼替佐米与靶向人类肿瘤差异分数的疗法相结合可以导致更有效的肿瘤对照。
Hypoxia is a dynamic feature of the tumor microenvironment that contributes to drug resistance and cancer progression. We previously showed that components of the Unfolded Protein Response (UPR) elicited by endoplasmic reticulum (ER) stress, are also activated by hypoxia in vitro and in animal and human patient tumors. Here, we report that ER stressors, such as thapsigargin or the clinically used proteasome inhibitor bortezomib, exhibit significantly higher cytotoxicity towards hypoxic compared to normoxic tumor cells, which is accompanied by enhanced activation of UPR effectors in vitro and UPR reporter activity in vivo. Treatment of cells with the translation inhibitor cycloheximide, which relieves ER load, ameliorated this enhanced cytotoxicity, indicating that the increased cytotoxicity is ER stress-dependent. The mode of cell death was cell-type dependent, since DLD1 colorectal carcinoma cells exhibited enhanced apoptosis, whereas in HeLa cervical carcinoma cells, activated autophagy blocked apoptosis and eventually led to necrosis. Pharmacologic or genetic ablation of autophagy increased the levels of apoptosis. These results demonstrate that hypoxic tumor cells, which are generally more resistant to genotoxic agents, are hypersensitive to proteasome inhibitors and suggest that combining bortezomib with therapies that target the normoxic fraction of human tumors can lead to more effective tumor control.