A role for ceramide glycosylation in resistance to oxaliplatin in colorectal cancer.
A role for ceramide glycosylation in resistance to oxaliplatin in colorectal cancer.
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DOI：
10.1016/j.yexcr.2020.111860
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发表时间：
2020-03-15
影响因子：
3.7
通讯作者：
Rosenberg DW
中科院分区：
文献类型：
--
作者：
Madigan JP;Robey RW;Poprawski JE;Huang H;Clarke CJ;Gottesman MM;Cabot MC;Rosenberg DW
越来越多的证据支持神经酰胺代谢酶葡糖神经酰胺合酶（GCS）在对多种化疗药物的耐药性中的作用。GCS是否有助于结直肠癌（CRC）的奥沙利铂耐药尚未确定。我们通过在两组奥沙利铂耐药的同基因CRC细胞系中检查GCS功能来解决这个潜在的重要临床问题。与亲本细胞系相比，奥沙利铂耐药细胞的GCS蛋白表达增加，与促存活神经酰胺代谢物葡萄糖神经酰胺（GlcCer）水平增加相关。通过RNAi介导的基因敲低抑制GCS表达导致细胞GlcCer水平降低，并恢复对奥沙利铂的敏感性。此外，与亲本细胞相比，奥沙利铂耐药CRC细胞在基础和奥沙利铂治疗后均显示出较低的神经酰胺水平。由GCS介导的神经酰胺糖基化形成的GlcCer是复杂鞘糖脂阵列的前体。在亲代和奥沙利铂耐药CRC细胞之间也观察到神经节苷脂（一种鞘糖脂家族）的细胞水平和种类差异。在奥沙利铂耐药CRC细胞系中也观察到Akt活化增加，以及抗凋亡蛋白生存素表达增加。最后，这项研究表明，GCS蛋白水平大大增加，在人类CRC标本相比，匹配，正常的结肠粘膜，高水平的UGCG基因表达显着相关的结直肠癌患者的无病生存率下降。这些发现揭示了GCS在奥沙利铂化疗敏感性中的重要细胞作用，并可能为增强CRC化疗药物的有效性提供新的细胞靶点。
There is growing evidence to support a role for the ceramide-metabolizing enzyme, glucosylceramide synthase (GCS), in resistance to a variety of chemotherapeutic agents. Whether GCS contributes to oxaliplatin resistance in colorectal cancer (CRC) has not yet been determined. We have addressed this potentially important clinical issue by examining GCS function in two panels of oxaliplatin-resistant, isogenic CRC cell lines. Compared to parental cell lines, oxaliplatin-resistant cells have increased expression of GCS protein associated with increased levels of the pro-survival ceramide metabolite, glucosylceramide (GlcCer). Inhibition of GCS expression by RNAi-mediated gene knockdown resulted in a reduction in cellular GlcCer levels, with restored sensitivity to oxaliplatin. Furthermore, oxaliplatin-resistant CRC cells displayed lower ceramide levels both basally and after treatment with oxaliplatin, compared to parental cells. GlcCer, formed by GCS-mediated ceramide glycosylation, is the precursor to a complex array of glycosphingolipids. Differences in cellular levels and species of gangliosides, a family of glycosphingolipids, were also seen between parental and oxaliplatin-resistant CRC cells. Increased Akt activation was also observed in oxaliplatin-resistant CRC cell lines, together with increased expression of the anti-apoptotic protein survivin. Finally, this study shows that GCS protein levels are greatly increased in human CRC specimens, compared to matched, normal colonic mucosa, and that high levels of UGCG gene expression are significantly associated with decreased disease-free survival in colorectal cancer patients. These findings uncover an important cellular role for GCS in oxaliplatin chemosensitivity and may provide a novel cellular target for augmenting chemotherapeutic drug effectiveness in CRC.
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DOI：
10.1016/j.bbalip.2013.09.007
发表时间：
2014-05
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
García-Barros M;Coant N;Truman JP;Snider AJ;Hannun YA
通讯作者：
Hannun YA
影响因子：
4.8
作者：
Lee WK;Kolesnick RN
通讯作者：
Kolesnick RN
影响因子：
4.8
作者：
Arcaro, Alexandre;Aubert, Muriel;Seckl, Michael J.
通讯作者：
Seckl, Michael J.
影响因子：
5.6
作者：
Giussani P;Tringali C;Riboni L;Viani P;Venerando B
通讯作者：
Venerando B
影响因子：
4.8
作者：
Kawamori, Toshihiko;Kaneshiro, Tatsuya;Obeid, Lina M.
通讯作者：
Obeid, Lina M.