Pharmacological inhibition of Ref-1 enhances the therapeutic sensitivity of papillary thyroid carcinoma to vemurafenib.
Pharmacological inhibition of Ref-1 enhances the therapeutic sensitivity of papillary thyroid carcinoma to vemurafenib.
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Ref-1 的药理抑制可增强甲状腺乳头状癌对维莫非尼的治疗敏感性
DOI：
10.1038/s41419-022-04550-0
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发表时间：
2022-02-08
影响因子：
9
通讯作者：
Gao M
中科院分区：
文献类型：
--
作者：
Hu L;Zhang J;Tian M;Kang N;Xu G;Zhi J;Ruan X;Hou X;Zhang W;Yi J;Ma W;Chang L;Tang T;Zheng X;Wei X;Gao M
使用BRAF抑制剂vemurafenib在治疗甲状腺癌（TC）中表现出耐药性，寻找更有效的多靶点联合治疗可能是一个重要的解决方案。在本研究中，我们发现Ref-1高表达与BRAF突变、淋巴结转移和TNM分期之间有很强的相关性。BRAF结构活化诱导的氧化应激环境上调Ref-1的表达，从而导致PTC对维罗非尼的内在抗性。联合抑制Ref-1氧化还原功能和BRAF可以增强vemurafenib的抗肿瘤作用，这是通过阻断Ref-1对BRAF蛋白的作用来实现的。此外，联合治疗可通过过度的AMPK蛋白活化引起自噬通量过载，在体外引起细胞衰老和细胞死亡。在基于细胞的肺转移性肿瘤模型和异种皮下肿瘤模型中，Ref-1和维罗非尼的体内联合给药抑制了PTC细胞的生长和转移。总的来说，我们的研究提供了证据表明，通过组成型激活PTC中的BRAF，Ref-1上调有助于对维罗非尼的内在耐药性。Ref-1氧化还原抑制剂和BRAF抑制剂的联合治疗可以使PTC对维罗非尼更敏感，并通过进一步抑制MAPK通路和激活过度自噬和相关衰老过程来增强维罗非尼的抗肿瘤作用。
The use of the BRAF inhibitor vemurafenib exhibits drug resistance in the treatment of thyroid cancer (TC), and finding more effective multitarget combination therapies may be an important solution. In the present study, we found strong correlations between Ref-1 high expression and BRAF mutation, lymph node metastasis, and TNM stage. The oxidative stress environment induced by structural activation of BRAF upregulates the expression of Ref-1, which caused intrinsic resistance of PTC to vemurafenib. Combination inhibition of the Ref-1 redox function and BRAF could enhance the antitumor effects of vemurafenib, which was achieved by blocking the action of Ref-1 on BRAF proteins. Furthermore, combination treatment could cause an overload of autophagic flux via excessive AMPK protein activation, causing cell senescence and cell death in vitro. And combined administration of Ref-1 and vemurafenib in vivo suppressed PTC cell growth and metastasis in a cell-based lung metastatic tumor model and xenogeneic subcutaneous tumor model. Collectively, our study provides evidence that Ref-1 upregulation via constitutive activation of BRAF in PTC contributes to intrinsic resistance to vemurafenib. Combined treatment with a Ref-1 redox inhibitor and a BRAF inhibitor could make PTC more sensitive to vemurafenib and enhance the antitumor effects of vemurafenib by further inhibiting the MAPK pathway and activating the excessive autophagy and related senescence process.
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影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
6.5
作者：
Lee, Bongyong;Sahoo, Anupama;Sawada, Junko;Marchica, John;Sahoo, Sanjay;Layng, Fabiana I. A. L.;Finlay, Darren;Mazar, Joseph;Joshi, Piyush;Komatsu, Masanobu;Vuori, Kristiina;de Jong, Petrus R.;Ray, Animesh;Perera, Ranjan J.
通讯作者：
Perera, Ranjan J.
影响因子：
7.7
作者：
Levy, Jean M. Mulcahy;Zahedi, Shadi;Thorburn, Andrew
通讯作者：
Thorburn, Andrew
影响因子：
5.8
作者：
Martin, S.;Dudek-Peric, A. M.;Agostinis, P.
通讯作者：
Agostinis, P.
影响因子：
64.8
作者：
Garcia-Prat, Laura;Martinez-Vicente, Marta;Munoz-Canoves, Pura
通讯作者：
Munoz-Canoves, Pura