FBW7 increases the chemosensitivity of pancreatic cancer cells to gemcitabine through upregulation of ENT1.
FBW7 increases the chemosensitivity of pancreatic cancer cells to gemcitabine through upregulation of ENT1.
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FBW7 通过上调 ENT1 增加胰腺癌细胞对吉西他滨的化疗敏感性
DOI：
10.3892/or.2017.5856
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发表时间：
2017-10
期刊：
影响因子：
4.2
通讯作者：
Xu J
中科院分区：
文献类型：
--
作者：
Hu Q;Qin Y;Zhang B;Liang C;Ji S;Shi S;Xu W;Xiang J;Liang D;Ni Q;Yu X;Xu J
F-box and WD repeat domain-containing 7（FBW7）是一种肿瘤抑制基因，在多种肿瘤中发现了其突变或表达降低。我们最近的研究发现，在胰腺癌中，KRAS突变通过磷酸化和随后的泛素化降低了FBW7的表达。此外，FBW7通过诱导硫氧还蛋白相互作用蛋白（TXNIP）（一种线粒体定位的肿瘤抑制因子）抑制胰腺癌中的有氧糖酵解。FBW7通过蛋白体降解髓细胞白血病-1（MCL-1）（一种抗凋亡因子）在抗凋亡和耐药性中的作用已被报道。然而，FBW7在胰腺癌对吉西他滨的化疗耐药性中的作用很少报道。在本研究中，我们证明了胰腺癌细胞中FBW7的过表达增加了对吉西他滨的敏感性。从机制上讲，FBW7通过在蛋白质水平而不是转录水平上调平衡型核苷转运蛋白1（ENT1）来促进吉西他滨敏感性。深入分析表明，ENT1蛋白水平可以通过溶酶体抑制而增加。综上所述，我们的结果表明，FBW7可能是通过诱导ENT1来改善吉西他滨疗效的靶点。
F-box and WD repeat domain-containing 7 (FBW7) has been characterized as a tumor suppressor, and its mutation or decreased expression has been observed in many types of human cancers. Our recent studies have uncovered that in pancreatic cancer, the KRAS mutation decreased FBW7 expression through phosphorylation and subsequent ubiquitination. Moreover, FBW7 inhibited aerobic glycolysis in pancreatic cancer via induction of thioredoxin-interacting protein (TXNIP), a mitochondrial localized tumor suppressor. The roles of FBW7 in anti-apoptosis and drug resistance via proteosomal degradation of myeloid cell leukemia-1 (MCL-1), which is an anti-apoptotic factor have been reported. However, the role of FBW7 in the chemotherapeutic resistance of pancreatic cancer to gemcitabine has seldom been reported. In the present study, we demonstrated that overexpression of FBW7 in pancreatic cancer cells rendered increased sensitivity to gemcitabine. Mechanistically, FBW7 promoted gemcitabine sensitivity via upregulation of equilibrative nucleoside transporter 1 (ENT1) at the protein level rather than the transcriptional level. In depth analysis demonstrated that the ENT1 protein level could be increased by lysosome inhibition. Taken together, our results demonstrated that FBW7 could be a target for improving the therapeutic efficacy of gemcitabine by induction of ENT1.
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影响因子：
4.3
作者：
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通讯作者：
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影响因子：
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ERK 激酶磷酸化胰腺癌中的肿瘤抑制因子 FBW7 并使其不稳定
影响因子：
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作者：
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影响因子：
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作者：
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