Autophagy inhibition radiosensitizes in vitro, yet reduces radioresponses in vivo due to deficient immunogenic signalling.
Autophagy inhibition radiosensitizes in vitro, yet reduces radioresponses in vivo due to deficient immunogenic signalling.
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DOI：
10.1038/cdd.2013.124
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发表时间：
2014-01
影响因子：
12.4
通讯作者：
中科院分区：
文献类型：
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作者：
临床肿瘤学在很大程度上依赖于放疗的使用，这往往导致仅仅短暂的反应，随后是局部或远处复发。解释辐射抗性的分子机制在很大程度上是难以捉摸的。在这里，我们确定了自噬在癌细胞对电离辐射的反应中的双重作用。一方面，我们观察到必需的自噬相关基因产物，如ATG5和Beclin 1的缺失，增加了人类或小鼠癌细胞系对辐照的敏感性，无论是在体外（自噬抑制增加辐射诱导的细胞死亡和降低克隆性存活），还是在体内，将这些细胞系移植到免疫缺陷小鼠体内（自噬抑制增强了放疗的肿瘤生长抑制作用）。另一方面，当在免疫功能正常的小鼠体内植入精通或缺乏自噬的肿瘤时，结果表明，有缺陷的自噬降低了放疗的效果。事实上，放疗引发了一种抗癌免疫反应，这种反应依赖于自噬诱导的ATP从应激或死亡的肿瘤细胞中释放出来，其特征是肿瘤床上密集的淋巴细胞浸润。瘤内注射一种体外三磷酸腺苷酶抑制剂可恢复放射治疗后自噬缺陷肿瘤的免疫浸润，提高电离照射的生长抑制作用。总之，我们的研究结果表明，除了细胞保护功能外，自噬还赋予肿瘤免疫原性，从而在免疫能力强的情况下放大放疗的疗效。这对药理学放射增敏剂的发展具有深远的意义。
Clinical oncology heavily relies on the use of radiotherapy, which often leads to merely transient responses that are followed by local or distant relapse. The molecular mechanisms explaining radioresistance are largely elusive. Here, we identified a dual role of autophagy in the response of cancer cells to ionizing radiation. On one hand, we observed that the depletion of essential autophagy-relevant gene products, such as ATG5 and Beclin 1, increased the sensitivity of human or mouse cancer cell lines to irradiation, both in vitro (where autophagy inhibition increased radiation-induced cell death and decreased clonogenic survival) and in vivo, after transplantation of the cell lines into immunodeficient mice (where autophagy inhibition potentiated the tumour growth-inhibitory effect of radiotherapy). On the other hand, when tumour proficient or deficient for autophagy were implanted in immunocompetent mice, it turned out that defective autophagy reduced the efficacy of radiotherapy. Indeed, radiotherapy elicited an anti-cancer immune response that was dependent on autophagy-induced ATP release from stressed or dying tumour cells and was characterized by dense lymphocyte infiltration of the tumour bed. Intratumoural injection of an ecto-ATPase inhibitor restored the immune infiltration of autophagy-deficient tumours post radiotherapy and improved the growth-inhibitory effect of ionizing irradiation. Altogether, our results reveal that beyond its cytoprotective function, autophagy confers immunogenic properties to tumours, hence amplifying the efficacy of radiotherapy in an immunocompetent context. This has far-reaching implications for the development of pharmacological radiosensitizers.
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影响因子：
11.2
作者：
Apel, Anja;Herr, Ingrid;Mayer, Andreas
通讯作者：
Mayer, Andreas
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1158/1078-0432.ccr-09-0589
发表时间：
2009-10-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Kim KW;Moretti L;Mitchell LR;Jung DK;Lu B
通讯作者：
Lu B
影响因子：
64.5
作者：
Mathew R;Karp CM;Beaudoin B;Vuong N;Chen G;Chen HY;Bray K;Reddy A;Bhanot G;Gelinas C;Dipaola RS;Karantza-Wadsworth V;White E
通讯作者：
White E
影响因子：
2.6
作者：
Chen, Y. S.;Song, H. X.;Fu, T.
通讯作者：
Fu, T.