Grabenbauer Felix, Katzer Astrid, Sisario Dmitri, Memmel Simon, Flentje Michael, Sukhorukov Vladimir L, Djuzenova Cholpon S
Department of Radiation Oncology, University Hospital of Würzburg, Würzburg, Germany.
Department of Biotechnology and Biophysics, University of Würzburg, Würzburg, Germany.
Oncotarget. 2018 Dec 21;9(100):37379-37392. doi: 10.18632/oncotarget.26436.
Targeting MEK protein in cancer cells usually leads to acquired resistance to MEK inhibitors and activation of the prosurvival protein Akt. Since both MEK and Akt are clients of the Hsp90 chaperone system, the present study explores the responses of irradiated lung carcinoma A549 and glioblastoma SNB19 cell lines to combined MEK and Hsp90 inhibition. Unexpectedly, the MEK inhibitor PD184352 administered 24 h prior to irradiation, enhanced cell survival through upregulation of not only MEK and Erk1/2 but also of Akt. In contrast, PD184352 added 1 h before irradiation strongly reduced the expression of Erk and did not upregulate Akt in both cell lines. As a result, the MEK inhibitor increased the radiosensitizing effect of the Hsp90 inhibitor NVP-AUY922 in glioblastoma SNB19 cells. Possible reasons for the enhanced cell killing under this short-term pretreatment schedule may be a down-regulation of Erk during or directly after irradiation, increased DNA damage and/or a strong G/M arrest 24 h after irradiation. In addition, an 1-h pretreatment with PD184352 and/or NVP-AUY922 under schedule II induced neither G arrest nor up-regulation of p-Akt in both cell lines as it did under schedule I. Yet, a long-term treatment with the MEK inhibitor alone caused a strong cytostatical effect. We conclude that the duration of drug pretreatment before irradiation plays a key role in the targeting of MEK in tumor cells. However, due to an aberrant activation of prosurvival proteins, the therapeutic window needs to be carefully defined, or a combination of inhibitors should be considered.
在癌细胞中靶向MEK蛋白通常会导致对MEK抑制剂产生获得性耐药，并激活促生存蛋白Akt。由于MEK和Akt都是Hsp90伴侣系统的作用对象，本研究探讨了受辐照的肺癌A549细胞系和胶质母细胞瘤SNB19细胞系对MEK和Hsp90联合抑制的反应。出乎意料的是，在辐照前24小时给予MEK抑制剂PD184352，不仅通过上调MEK和Erk1/2，还通过上调Akt来提高细胞存活率。相比之下，在辐照前1小时添加PD184352可强烈降低Erk的表达，并且在两种细胞系中均未上调Akt。结果，MEK抑制剂增强了Hsp90抑制剂NVP-AUY922对胶质母细胞瘤SNB19细胞的放射增敏作用。在这种短期预处理方案下增强细胞杀伤的可能原因可能是在辐照期间或辐照后直接下调Erk、增加DNA损伤和/或在辐照后24小时出现强烈的G/M期阻滞。此外，在方案II下用PD184352和/或NVP-AUY922进行1小时预处理，在两种细胞系中既未诱导G期阻滞，也未像在方案I下那样上调p-Akt。然而，单独使用MEK抑制剂进行长期治疗会产生强烈的细胞抑制作用。我们得出结论，辐照前药物预处理的持续时间在肿瘤细胞中靶向MEK方面起着关键作用。然而，由于促生存蛋白的异常激活，需要仔细定义治疗窗口，或者应考虑联合使用抑制剂。
