紫杉醇诱导乳腺癌细胞凋亡调节氨基酸运输。
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吴Y,沈D,陈Z,克莱顿年代,Vadgama合资企业
紫杉醇诱导乳腺癌细胞凋亡调节氨基酸运输。
细胞凋亡。2007年3月,12 (3):593 - 612。Epub 2006年12月29日。
- PubMed ID
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17195090 (在PubMed]
- 文摘
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主要从紫杉醇治疗的结果是诱导肿瘤细胞凋亡。然而,代谢反应Taxol-induced细胞凋亡是知之甚少。在这项研究中,我们假设在特定氨基酸转运蛋白改变可能影响Taxol-induced在乳腺癌细胞凋亡。在这种情况下,鉴于运输车的活动可以作为生物标志物可以提供药物治疗反应的生物评估。我们已经检查了机制负责Taxol-induced中性氨基酸吸收乳腺癌细胞,如MCF-7 BT474, MDAMB231 T47D。生化和分子研究包括:(1)生长抑制(MTT);(2)传输动力学:(3)substrate-specific抑制;(4)thiol-modifying代理NEM和NPM的影响;(5)氨基酸转运蛋白的基因表达;(6)凋亡检测。 Our data show that Taxol treatment of MCF-7 cells induced a transient increase in Na(+)-dependent transport of the neutral amino acid transporter B0 at both gene and protein level. This increase was attenuated by blocking the transporter in the presence of high concentrations of the substrate amino acid. Other neutral amino acid transporters such as ATA2 (System A) and ASC were not altered. Amino acid starvation resulted in the expected up-regulation of System A (ATA2) gene, but not for B0 and ASC. B0 was significantly down regulated. Taxol treatment had no significant effect on the uptake of arginine and glutamate as measured by System y(+) and X(-) (GC) respectively. Tunel assays and FACS cell cycle analysis demonstrated that both Taxol- and doxorubicin-induced upregulation of B0 transporter gene with accompanying increase in cell apoptosis, could be reversed partially by blocking the B0 transporter with high concentration of alanine, and/or by inhibiting the caspase pathway. Both Taxol and doxorubicin treatment caused a significant decrease in S-phase of the cell cycle. However, Taxol-induced an increase primarily in the G2 fraction while doxorubicin caused increase in G1/G0 together with a small increase in G2. In summary, our study showed that Taxol induced apoptosis in several breast cancer cells results in activation of amino acid transporter System B0 at both gene and protein level. Similar response was observed with another chemotherapeutic agent Doxorubicin, suggesting that this increase is in response to apoptosis, and not only due to changes in cell cycle related events.