不是所有的腫瘤區(qū)域都有相等的氧水平,，這在臨床上的一個重要應(yīng)用是大面積的腫瘤處于低氧環(huán)境與預(yù)測困難和治療應(yīng)答有關(guān),。
加拿大多倫多大學(xué)的研究小組已經(jīng)確定，非折疊蛋白應(yīng)答通路（the unfolded protein response pathway）,，在低氧和抗癌輻射療法中參與保護人類腫瘤細胞。這項研究的負責(zé)人是Bradly Wouters。
進一步的分析表明,，該非折疊蛋白應(yīng)答通路增加了兩類蛋白的表達，這兩種蛋白參與細胞的自我吞噬過程,，該過程會及時保護細胞,。
此外，細胞自我吞噬的抑制激活了培養(yǎng)的人類腫瘤細胞缺氧適應(yīng)性以及人類腫瘤細胞對輻射的抑制,。這項研究的負責(zé)人表示,，靶向定位他們識別的這種分子或能有助于臨床研究。
這項研究結(jié)果發(fā)表在Journal of Clinical Investigation上,，感興趣的讀者可以參閱以下文獻,。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
