Functional disruption of the Golgi apparatus protein ARF1 sensitizes MDA-MB-231 breast cancer cells to the antitumor drugs Actinomycin D and Vinblastine through ERK and AKT signaling.
Functional disruption of the Golgi apparatus protein ARF1 sensitizes MDA-MB-231 breast cancer cells to the antitumor drugs Actinomycin D and Vinblastine through ERK and AKT signaling.
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DOI：
10.1371/journal.pone.0195401
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Mardones GA
中科院分区：
文献类型：
--
作者：
Luchsinger C;Aguilar M;Burgos PV;Ehrenfeld P;Mardones GA
越来越多的证据表明高尔基体在肿瘤中起着积极的作用，但对它在肿瘤发生转化中的作用还没有全面的认识。与此同时，高尔基体被公认为是整合其蛋白质和脂质生物合成功能的枢纽，用于癌细胞中细胞增殖和迁移的信号转导。然而，高尔基体在癌细胞中的活性功能尚未被充分评价为联合治疗的靶点。在这里，我们分析了扰乱高尔基体对MDA-MB-231乳腺癌细胞系对药物放线菌素D和长春碱的敏感性的影响。我们破坏了ARF 1的功能，ARF 1是高尔基体稳态所必需的蛋白质。我们发现ARF 1-Q71 L突变体的表达增加了MDA-MB-231细胞对放线菌素D和长春碱的敏感性，导致细胞增殖和细胞迁移减少，以及凋亡增加。同样地，用放线菌素D或长春碱和布雷菲德菌素A或杀高尔基体剂A（两种ARF 1功能的破坏剂）联合处理细胞，对细胞增殖、细胞迁移和细胞凋亡产生类似的作用。有趣的是，每种联合治疗对ERK 1/2和AKT信号传导具有不同的影响，如磷酸化ERK 1/2或磷酸化AKT水平降低所示。我们的研究结果表明，破坏高尔基体功能可以作为一种策略，敏感的癌细胞化疗。
Increasing evidence indicates that the Golgi apparatus plays active roles in cancer, but a comprehensive understanding of its functions in the oncogenic transformation has not yet emerged. At the same time, the Golgi is becoming well recognized as a hub that integrates its functions of protein and lipid biosynthesis to signal transduction for cell proliferation and migration in cancer cells. Nevertheless, the active function of the Golgi apparatus in cancer cells has not been fully evaluated as a target for combined treatment. Here, we analyzed the effect of perturbing the Golgi apparatus on the sensitivity of the MDA-MB-231 breast cancer cell line to the drugs Actinomycin D and Vinblastine. We disrupted the function of ARF1, a protein necessary for the homeostasis of the Golgi apparatus. We found that the expression of the ARF1-Q71L mutant increased the sensitivity of MDA-MB-231 cells to both Actinomycin D and Vinblastine, resulting in decreased cell proliferation and cell migration, as well as in increased apoptosis. Likewise, the combined treatment of cells with Actinomycin D or Vinblastine and Brefeldin A or Golgicide A, two disrupting agents of the ARF1 function, resulted in similar effects on cell proliferation, cell migration and apoptosis. Interestingly, each combined treatment had distinct effects on ERK1/2 and AKT signaling, as indicated by the decreased levels of either phospho-ERK1/2 or phospho-AKT. Our results suggest that disruption of Golgi function could be used as a strategy for the sensitization of cancer cells to chemotherapy.
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影响因子：
--
作者：
Davis JE;Xie X;Guo J;Huang W;Chu WM;Huang S;Teng Y;Wu G
通讯作者：
Wu G
影响因子：
2
作者：
Archambaud, S;Aphecetche-Julienne, K;Guingant, A
通讯作者：
Guingant, A
DOI：
10.1073/pnas.89.14.6408
发表时间：
1992-07-15
影响因子：
11.1
作者：
DONALDSON, JG;CASSEL, D;KLAUSNER, RD
通讯作者：
KLAUSNER, RD
影响因子：
3.6
作者：
BERNHARDT, G;REILE, H;SCHOENENBERGER, H
通讯作者：
SCHOENENBERGER, H
影响因子：
64.8
作者：
DONALDSON, JG;FINAZZI, D;KLAUSNER, RD
通讯作者：
KLAUSNER, RD