Human GM3 Synthase Attenuates Taxol-Triggered Apoptosis Associated with Downregulation of Caspase-3 in Ovarian Cancer Cells.
Human GM3 Synthase Attenuates Taxol-Triggered Apoptosis Associated with Downregulation of Caspase-3 in Ovarian Cancer Cells.
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DOI：
10.4236/jct.2012.35065
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发表时间：
2012-10
期刊：
影响因子：
--
通讯作者：
Safa AR
中科院分区：
文献类型：
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作者：
Huang S;Bijangi-Vishehsaraei K;Saadatzadeh MR;Safa AR
紫杉醇（紫杉醇）可抑制多种癌细胞的增殖并诱导细胞凋亡，但它也会上调细胞保护蛋白和/或通路，从而损害其治疗效果。通过在 SKOV3 人卵巢癌细胞系中克隆和过表达该酶，用紫杉醇处理 SKOV3 和转染子 (SKOV3/GS)，并测定细胞凋亡、细胞存活、克隆形成能力和 caspase-3 激活，确定 GM3 合酶（α2,3-唾液酸转移酶，ST3Gal V）在减弱紫杉醇诱导的细胞凋亡和引发耐药性中的作用。在本报告中，我们证明紫杉醇治疗会导致细胞凋亡，这与 caspase-3 激活相关。紫杉醇治疗上调了人 GM3 合酶的表达，该酶将唾液酸转移为乳糖神经酰胺。此外，我们克隆了全长 GM3 合酶基因，并首次表明 GM3 合酶的强制表达可减弱紫杉醇诱导的细胞凋亡并增加 SKOV3 细胞对紫杉醇的抵抗力。 GM3 合酶过度表达抑制紫杉醇触发的 caspase-3 激活，表明 GM3 合酶的上调可防止细胞凋亡，从而降低紫杉醇治疗的功效。
Taxol (paclitaxel) inhibits proliferation and induces apoptosis in a variety of cancer cells, but it also upregulates cytoprotective proteins and/or pathways that compromise its therapeutic efficacy. The roles of GM3 synthase (α2,3-sialyltransferase, ST3Gal V) in attenuating Taxol-induced apoptosis and triggering drug resistance were determined by cloning and overexpressing this enzyme in the SKOV3 human ovarian cancer cell line, treating SKOV3 and the transfectants (SKOV3/GS) with Taxol and determining apoptosis, cell survival, clonogenic ability, and caspase-3 activation. In this report, we demonstrated that Taxol treatment resulted in apoptosis which was associated with caspase-3 activation. Taxol treatment upregulated the expression of human GM3 synthase, an enzyme that transfers a sialic acid to lactosylceramide. Moreover, we cloned the full-length GM3 synthase gene and showed for the first time that forced expression of GM3 synthase attenuated Taxol-induced apoptosis and increased resistance to Taxol in SKOV3 cells. GM3 synthase overexpression inhibited Taxol-triggered caspase-3 activation, revealing that upregulation of GM3 synthase prevents apoptosis and hence reduces the efficacy of Taxol therapy.