17-AAG inhibits vemurafenib-associated MAP kinase activation and is synergistic with cellular immunotherapy in a murine melanoma model.
17-AAG inhibits vemurafenib-associated MAP kinase activation and is synergistic with cellular immunotherapy in a murine melanoma model.
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DOI：
10.1371/journal.pone.0191264
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Hornyak TJ
中科院分区：
文献类型：
--
作者：
Joshi SS;Jiang S;Unni E;Goding SR;Fan T;Antony PA;Hornyak TJ
热休克蛋白90（HSP 90）是一种分子伴侣，其稳定客户蛋白，在肿瘤生长中起重要作用。17-烯丙基氨基-17-去甲氧基格尔德霉素（17-AAG）是一种HSP 90 ATP酶活性抑制剂，它占据HSP 90的ATP结合位点，引起构象变化，使客户蛋白不稳定，并将其导向蛋白体降解。恶性黑色素瘤具有活性RAF-MEK-ERK信号传导，其可以通过BRAF中的激活突变（BRAFV 600 E）或通过BRAF上游的信号转导的激活而发生。先前的工作表明，17-AAG抑制BRAFV 600 E和BRAF野生型（BRAFWT）黑色素瘤中的细胞生长，尽管关于BRAFV 600 E和BRAFWT对HSP 90活性的稳定性的依赖性存在相互矛盾的报道。在这里，我们证明了BRAFWT和CRAF在BRAFWT，NRAS突变的黑色素瘤细胞中被HSP 90结合。在大多数NRAS突变型黑素瘤细胞中，17-AAG对HSP 90的抑制通过使CRAF而不是BRAFWT不稳定来抑制ERK信号传导和细胞生长。高选择性BRAFV 600 E抑制剂PLX 4032（vemurafenib）可抑制突变型BRAF黑色素瘤细胞中的ERK信号传导和细胞生长，但矛盾的是，可增强野生型BRAF细胞中的信号传导。在我们的研究中，我们检查了17-AAG是否可以抑制BRAFWT黑色素瘤细胞中PLX 4032增强的ERK信号传导。如所预期的，PLX 4032单独增强BRAFWT黑素瘤细胞系Mel-Juso、SK-Mel-2和SK-Mel-30中的ERK信号传导，并抑制BRAFV 600 E A375细胞中的信号传导和细胞生长。然而，17-AAG抑制HSP 90抑制PLX 4032增强的ERK信号传导，并通过使CRAF不稳定来抑制细胞生长。令人惊讶的是，17-AAG还刺激了SK-Mel-30细胞中的黑色素产生，并在所研究的所有三种BRAFWT细胞系以及B16 F10小鼠黑色素瘤细胞中增强了TYRP 1和DCT表达，而不刺激TYR产生。在体内，17-AAG和针对Tyrp 1的细胞免疫疗法的组合与单独的任一种疗法相比增强了对肿瘤生长的抑制。我们的研究支持17-AAG和HSP 90抑制在增强黑色素瘤细胞免疫治疗中的作用。
Heat shock protein 90 (HSP90) is a molecular chaperone which stabilizes client proteins with important roles in tumor growth. 17-allylamino-17-demethoxygeldanamycin (17-AAG), an inhibitor of HSP90 ATPase activity, occupies the ATP binding site of HSP90 causing a conformational change which destabilizes client proteins and directs them towards proteosomal degradation. Malignant melanomas have active RAF-MEK-ERK signaling which can occur either through an activating mutation in BRAF (BRAFV600E) or through activation of signal transduction upstream of BRAF. Prior work showed that 17-AAG inhibits cell growth in BRAFV600E and BRAF wildtype (BRAFWT) melanomas, although there were conflicting reports about the dependence of BRAFV600E and BRAFWT upon HSP90 activity for stability. Here, we demonstrate that BRAFWT and CRAF are bound by HSP90 in BRAFWT, NRAS mutant melanoma cells. HSP90 inhibition by 17-AAG inhibits ERK signaling and cell growth by destabilizing CRAF but not BRAFWT in the majority of NRAS mutant melanoma cells. The highly-selective BRAFV600E inhibitor, PLX4032 (vemurafenib), inhibits ERK signaling and cell growth in mutant BRAF melanoma cells, but paradoxically enhances signaling in cells with wild-type BRAF. In our study, we examined whether 17-AAG could inhibit PLX4032-enhanced ERK signaling in BRAFWT melanoma cells. As expected, PLX4032 alone enhanced ERK signaling in the BRAFWT melanoma cell lines Mel-Juso, SK-Mel-2, and SK-Mel-30, and inhibited signaling and cell growth in BRAFV600E A375 cells. However, HSP90 inhibition by 17-AAG inhibited PLX4032-enhanced ERK signaling and inhibited cell growth by destabilizing CRAF. Surprisingly, 17-AAG also stimulated melanin production in SK-Mel-30 cells and enhanced TYRP1 and DCT expression without stimulating TYR production in all three BRAFWT cell lines studied as well as in B16F10 mouse melanoma cells. In vivo, the combination of 17-AAG and cellular immunotherapy directed against Tyrp1 enhanced the inhibition of tumor growth compared to either therapy alone. Our studies support a role for 17-AAG and HSP90 inhibition in enhancing cellular immunotherapy for melanoma.
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影响因子：
11.2
作者：
Nissan MH;Pratilas CA;Jones AM;Ramirez R;Won H;Liu C;Tiwari S;Kong L;Hanrahan AJ;Yao Z;Merghoub T;Ribas A;Chapman PB;Yaeger R;Taylor BS;Schultz N;Berger MF;Rosen N;Solit DB
通讯作者：
Solit DB
影响因子：
4.4
作者：
Babchia, Narjes;Calipel, Armelle;Mascarelli, Frederic
通讯作者：
Mascarelli, Frederic
DOI：
10.1038/skinbio.2011.4
发表时间：
2011-11-17
期刊：
The Journal of investigative dermatology
影响因子：
--
作者：
Hearing VJ
通讯作者：
Hearing VJ
DOI：
10.1084/jem.20030590
发表时间：
2003-08-18
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Overwijk WW;Theoret MR;Finkelstein SE;Surman DR;de Jong LA;Vyth-Dreese FA;Dellemijn TA;Antony PA;Spiess PJ;Palmer DC;Heimann DM;Klebanoff CA;Yu Z;Hwang LN;Feigenbaum L;Kruisbeek AM;Rosenberg SA;Restifo NP
通讯作者：
Restifo NP
影响因子：
8
作者：
Basso, AD;Solit, DB;Rosen, N
通讯作者：
Rosen, N