The unfolded protein response impacts melanoma progression by enhancing FGF expression and can be antagonized by a chemical chaperone.
The unfolded protein response impacts melanoma progression by enhancing FGF expression and can be antagonized by a chemical chaperone.
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DOI：
10.1038/s41598-017-17888-9
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发表时间：
2017-12-13
影响因子：
4.6
通讯作者：
Röhrl C
中科院分区：
文献类型：
--
作者：
Eigner K;Filik Y;Mark F;Schütz B;Klambauer G;Moriggl R;Hengstschläger M;Stangl H;Mikula M;Röhrl C
黑色素瘤进展的机制尚不清楚。在这里，我们研究了未折叠蛋白反应(UPR) -一种在癌变过程中发挥模糊作用的信号级联-在恶性黑色素瘤中的影响。我们鉴定了含有brafv600e突变的等基因患者源性黑色素瘤细胞系作为模型系统，以研究内在UPR在黑色素瘤进展中的作用。我们发现，与非转移细胞相比，转移细胞中UPR的三种效应通路（ATF6， PERK和IRE1）的活性增加。upr活性的增加与应对内质网应激的灵活性增加有关。在黑色素瘤患者中，ATF6-和PERK-通路的活性，而不是ire -通路的活性，与较差的生存率相关。通过全基因组表达分析，我们发现UPR是FGF1和FGF2表达和细胞迁移的诱导剂。使用化学伴侣4-苯基丁酸（4-PBA）拮抗UPR可降低FGF表达并抑制细胞迁移和活力。在人黑色素瘤中，FGF的表达与ATF6和PERK的活性一致呈正相关。我们得出结论，慢性UPR刺激FGF/FGF受体信号轴并促进黑色素瘤的进展。因此，开发有效的化学伴侣来对抗UPR可能是靶向黑色素瘤的治疗方法。
The mechanisms hallmarking melanoma progression are insufficiently understood. Here we studied the impact of the unfolded protein response (UPR) - a signalling cascade playing ambiguous roles in carcinogenesis - in melanoma malignancy. We identified isogenic patient-derived melanoma cell lines harboring BRAFV600E-mutations as a model system to study the role of intrinsic UPR in melanoma progression. We show that the activity of the three effector pathways of the UPR (ATF6, PERK and IRE1) was increased in metastatic compared to non-metastatic cells. Increased UPR-activity was associated with increased flexibility to cope with ER stress. The activity of the ATF6- and the PERK-, but not the IRE-pathway, correlated with poor survival in melanoma patients. Using whole-genome expression analysis, we show that the UPR is an inducer of FGF1 and FGF2 expression and cell migration. Antagonization of the UPR using the chemical chaperone 4-phenylbutyric acid (4-PBA) reduced FGF expression and inhibited cell migration and viability. Consistently, FGF expression positively correlated with the activity of ATF6 and PERK in human melanomas. We conclude that chronic UPR stimulates the FGF/FGF-receptor signalling axis and promotes melanoma progression. Hence, the development of potent chemical chaperones to antagonize the UPR might be a therapeutic approach to target melanoma.
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影响因子：
4.7
作者：
Li FZ;Dhillon AS;Anderson RL;McArthur G;Ferrao PT
通讯作者：
Ferrao PT
影响因子：
5.6
作者：
Bu Y;Diehl JA
通讯作者：
Diehl JA
DOI：
10.1186/bcr3373
发表时间：
2013-01-07
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Nagelkerke A;Bussink J;Mujcic H;Wouters BG;Lehmann S;Sweep FC;Span PN
通讯作者：
Span PN
影响因子：
21.3
作者：
通讯作者：
--
DOI：
10.1073/pnas.0905139106
发表时间：
2009-12-01
影响因子：
11.1
作者：
Bogunovic, Dusan;O'Neill, David W.;Bhardwaj, Nina
通讯作者：
Bhardwaj, Nina