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转谷氨酰胺酶2的代偿性增加导致对mTOR抑制剂治疗产生耐药性。

Compensatory Increase of Transglutaminase 2 Is Responsible for Resistance to mTOR Inhibitor Treatment.

作者信息

Cao Jingwen, Huang Wenlong

机构信息

China Pharmaceutical University, Nanjing, Jiangsu Province, People's Republic of China.

Chinese Academy of Medical Sciences, Beijing, People's Republic of China.

出版信息

PLoS One. 2016 Feb 12;11(2):e0149388. doi: 10.1371/journal.pone.0149388. eCollection 2016.

Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) plays a crucial role in controlling cell growth and homeostasis. Deregulation of mTOR signaling is frequently observed in some cancers, making it an attractive drug target for cancer therapy. Although mTORC1 inhibitor rapalog-based therapy has shown positive results in various pre-clinical animal cancer studies, tumors rebound upon treatment discontinuation. Moreover, several recent clinical trials showed that the mTORC1 inhibitors rapamycin and rapalog only reduce the capacity for cell proliferation without promoting cell death, consistent with the concept that rapamycin is cytostatic and reduces disease progression but is not cytotoxic. It is imperative that rapamycin-regulated events and additional targets for more effective drug combinations be identified. Here, we report that rapamycin treatment promotes a compensatory increase in transglutaminase 2 (TGM2) levels in mTORC1-driven tumors. TGM2 inhibition potently sensitizes mTORC1-hyperactive cancer cells to rapamycin treatment, and a rapamycin-induced autophagy blockade inhibits the compensatory TGM2 upregulation. More importantly, tumor regression was observed in MCF-7-xenograft tumor-bearing mice treated with both mTORC1 and TGM2 inhibitors compared with those treated with either a single inhibitor or the vehicle control. These results demonstrate a critical role for the compensatory increase in transglutaminase 2 levels in promoting mTORC1 inhibitor resistance and suggest that rational combination therapy may potentially suppress cancer therapy resistance.

摘要

雷帕霉素复合物1(mTORC1)的作用机制靶点在控制细胞生长和体内平衡中起着关键作用。mTOR信号失调在某些癌症中经常被观察到,这使其成为癌症治疗中一个有吸引力的药物靶点。尽管基于mTORC1抑制剂雷帕霉素类似物的疗法在各种临床前动物癌症研究中已显示出积极效果,但在治疗中断后肿瘤会复发。此外,最近的几项临床试验表明,mTORC1抑制剂雷帕霉素和雷帕霉素类似物仅降低细胞增殖能力,而不促进细胞死亡,这与雷帕霉素具有细胞生长抑制作用、可减缓疾病进展但无细胞毒性的概念一致。必须确定雷帕霉素调节的事件以及更有效药物组合的其他靶点。在此,我们报告雷帕霉素治疗会促进mTORC1驱动的肿瘤中转谷氨酰胺酶2(TGM2)水平的代偿性增加。抑制TGM2可使mTORC1过度活跃的癌细胞对雷帕霉素治疗高度敏感,而雷帕霉素诱导的自噬阻断可抑制TGM2的代偿性上调。更重要的是,与单独使用一种抑制剂或溶剂对照相比,用mTORC1和TGM2抑制剂联合治疗的MCF-7异种移植荷瘤小鼠出现了肿瘤消退。这些结果表明转谷氨酰胺酶2水平的代偿性增加在促进mTORC1抑制剂耐药性方面起着关键作用,并表明合理的联合治疗可能潜在地抑制癌症治疗耐药性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d60c/4752276/2a4d1fb8d43b/pone.0149388.g001.jpg

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