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癌细胞在低氧水平自我保护的机制
分类:国际医学技术 来源:本站编辑部 作者:med00 职称:
摘要:
靶向定位他们识别的这种分子或能有助于临床研究。

不是所有的肿瘤区域都有相等的氧水平,这在临床上的一个重要应用是大面积的肿瘤处于低氧环境与预测困难和治疗应答有关。

加拿大多伦多大学的研究小组已经确定,非折叠蛋白应答通路(the unfolded protein response pathway),在低氧和抗癌辐射疗法中参与保护人类肿瘤细胞。这项研究的负责人是Bradly Wouters。

进一步的分析表明,该非折叠蛋白应答通路增加了两类蛋白的表达,这两种蛋白参与细胞的自我吞噬过程,该过程会及时保护细胞。

此外,细胞自我吞噬的抑制激活了培养的人类肿瘤细胞缺氧适应性以及人类肿瘤细胞对辐射的抑制。这项研究的负责人表示,靶向定位他们识别的这种分子或能有助于临床研究。

这项研究结果发表在Journal of Clinical Investigation上,感兴趣的读者可以参阅以下文献。

原始出处:

J. Clin. Invest. doi:10.1172/JCI40027.

The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5

Kasper M.A. Rouschop1, Twan van den Beucken1,2, Ludwig Dubois1,3, Hanneke Niessen4, Johan Bussink5, Kim Savelkouls1, Tom Keulers1, Hilda Mujcic1, Willy Landuyt6, Jan Willem Voncken4, Philippe Lambin1, Albert J. van der Kogel5, Marianne Koritzinsky1,2,7 and Bradly G. Wouters1,2,7,8,9

1Department of Radiation Oncology (Maastro Lab), GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.
2Division of Signaling Biology, Ontario Cancer Institute/Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada.
3Department of Nuclear Medicine, University Hospital Gasthuisberg and KU Leuven, Leuven, Belgium.
4Department of Molecular Genetics, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.
5Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
6Laboratory of Experimental Radiotherapy, Department of Oncology, University Hospital Gasthuisberg and KU Leuven, Leuven, Belgium.
7Department of Radiation Oncology and
8Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
9Selective Therapeutics Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.

Tumor hypoxia is a common microenvironmental factor that adversely influences tumor phenotype and treatment response. Cellular adaptation to hypoxia occurs through multiple mechanisms, including activation of the unfolded protein response (UPR). Recent reports have indicated that hypoxia activates a lysosomal degradation pathway known as autophagy, and here we show that the UPR enhances the capacity of hypoxic tumor cells to carry out autophagy, and that this promotes their survival. In several human cancer cell lines, hypoxia increased transcription of the essential autophagy genes microtubule-associated protein 1 light chain 3β (MAP1LC3B) and autophagy-related gene 5 (ATG5) through the transcription factors ATF4 and CHOP, respectively, which are regulated by PKR-like ER kinase (PERK, also known as EIF2AK3). MAP1LC3B and ATG5 are not required for initiation of autophagy but mediate phagophore expansion and autophagosome formation. We observed that transcriptional induction of MAP1LC3B replenished MAP1LC3B protein that was turned over during extensive hypoxia-induced autophagy. Correspondingly, cells deficient in PERK signaling failed to transcriptionally induce MAP1LC3B and became rapidly depleted of MAP1LC3B protein during hypoxia. Consistent with these data, autophagy and MAP1LC3B induction occurred preferentially in hypoxic regions of human tumor xenografts. Furthermore, pharmacological inhibition of autophagy sensitized human tumor cells to hypoxia, reduced the fraction of viable hypoxic tumor cells, and sensitized xenografted human tumors to irradiation. Our data therefore demonstrate that the UPR is an important mediator of the hypoxic tumor microenvironment and that it contributes to resistance to treatment through its ability to facilitate autophagy.

 

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浏览次数:5061次   发布日期:2009-12-24

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