Glucosylceramide synthase upregulates MDR1 expression in the regulation of cancer drug resistance through cSrc and beta-catenin signaling.
Glucosylceramide synthase upregulates MDR1 expression in the regulation of cancer drug resistance through cSrc and beta-catenin signaling.
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DOI：
10.1186/1476-4598-9-145
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发表时间：
2010-06-11
期刊：
影响因子：
37.3
通讯作者：
Jazwinski SM
中科院分区：
文献类型：
--
作者：
Liu YY;Gupta V;Patwardhan GA;Bhinge K;Zhao Y;Bao J;Mehendale H;Cabot MC;Li YT;Jazwinski SM
耐药是肿瘤细胞在抗癌药物的胁迫下多基因相互作用的结果。MDR 1过表达最常在耐药癌症中检测到，并伴有其他基因改变，包括葡萄糖神经酰胺合酶（GCS）增强。MDR 1编码P-糖蛋白，其挤出抗癌药物。MDR 1的多态性破坏了P-糖蛋白拮抗剂的作用，并限制了临床试验中耐药逆转的成功。GCS将神经酰胺转化为葡糖神经酰胺，减少神经酰胺诱导的细胞凋亡的影响，并增加鞘糖脂（GSL）的合成。了解MDR 1过度表达的分子机制及其与GCS的相互作用可能会找到逆转耐药性的有效方法。MDR 1和GCS在耐药乳腺癌、卵巢癌、宫颈癌和结肠癌细胞中同时过表达;使用新型混合骨架寡核苷酸（MBO-asGCS）沉默GCS使这四种耐药细胞系对阿霉素敏感。这种致敏作用与MDR 1表达降低和阿霉素蓄积增加相关。阿霉素治疗诱导GCS和MDR 1在肿瘤中的表达，但MBO-asGCS治疗消除了耐药肿瘤（NCI/ADR-RES）的“体内”生长。MBO-asGCS可抑制GCS诱导的MDR 1表达，并对阿霉素敏感。MBO-asGCS对正常小肠P-糖蛋白无明显影响，但使肿瘤P-糖蛋白表达和药物外排功能分别降低4倍和8倍。GCS瞬时转染在OVCAR-8癌细胞中以剂量依赖性方式诱导MDR 1过表达并增加P-糖蛋白流出。GSL谱分析、globotriaosylceramide合成酶的沉默和信号通路的评估表明，GCS转染显著增加GSL富集微结构域（GEM）上globo系列GSL（globotriaosylceramide Gb 3、globotetraosylceramide Gb 4），激活cSrc激酶，降低β-catenin磷酸化，并增加核β-catenin。因此，这些增加了MDR 1启动子的激活及其表达。相反，MBO-asGCS处理降低globo系列GSL（Gb 3、Gb 4）、cSrc激酶和核β-catenin，并以剂量依赖性模式抑制MDR-1表达。这项研究首次证明，GCS上调MDR 1表达调节癌症的耐药性。GSL，特别是globo系列GSL通过cSrc和β-catenin信号通路介导MDR 1基因表达。
Drug resistance is the outcome of multiple-gene interactions in cancer cells under stress of anticancer agents. MDR1 overexpression is most commonly detected in drug-resistant cancers and accompanied with other gene alterations including enhanced glucosylceramide synthase (GCS). MDR1 encodes for P-glycoprotein that extrudes anticancer drugs. Polymorphisms of MDR1 disrupt the effects of P-glycoprotein antagonists and limit the success of drug resistance reversal in clinical trials. GCS converts ceramide to glucosylceramide, reducing the impact of ceramide-induced apoptosis and increasing glycosphingolipid (GSL) synthesis. Understanding the molecular mechanisms underlying MDR1 overexpression and how it interacts with GCS may find effective approaches to reverse drug resistance. MDR1 and GCS were coincidently overexpressed in drug-resistant breast, ovary, cervical and colon cancer cells; silencing GCS using a novel mixed-backbone oligonucleotide (MBO-asGCS) sensitized these four drug-resistant cell lines to doxorubicin. This sensitization was correlated with the decreased MDR1 expression and the increased doxorubicin accumulation. Doxorubicin treatment induced GCS and MDR1 expression in tumors, but MBO-asGCS treatment eliminated "in-vivo" growth of drug-resistant tumor (NCI/ADR-RES). MBO-asGCS suppressed the expression of MDR1 with GCS and sensitized NCI/ADR-RES tumor to doxorubicin. The expression of P-glycoprotein and the function of its drug efflux of tumors were decreased by 4 and 8 times after MBO-asGCS treatment, even though this treatment did not have a significant effect on P-glycoprotein in normal small intestine. GCS transient transfection induced MDR1 overexpression and increased P-glycoprotein efflux in dose-dependent fashion in OVCAR-8 cancer cells. GSL profiling, silencing of globotriaosylceramide synthase and assessment of signaling pathway indicated that GCS transfection significantly increased globo series GSLs (globotriaosylceramide Gb3, globotetraosylceramide Gb4) on GSL-enriched microdomain (GEM), activated cSrc kinase, decreased β-catenin phosphorylation, and increased nuclear β-catenin. These consequently increased MDR1 promoter activation and its expression. Conversely, MBO-asGCS treatments decreased globo series GSLs (Gb3, Gb4), cSrc kinase and nuclear β-catenin, and suppressed MDR-1 expression in dose-dependent pattern. This study demonstrates, for the first time, that GCS upregulates MDR1 expression modulating drug resistance of cancer. GSLs, in particular globo series GSLs mediate gene expression of MDR1 through cSrc and β-catenin signaling pathway.
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