Mostaq Md Saqline, Kang Lin, Patwardhan Gauri A, Zhao Yunfeng, Shi Runhua, Liu Yong-Yu
School of Basic Pharmaceutical and Toxicological Sciences, University of Louisiana at Monroe, Monroe, LA 71201, USA.
Department of Biomedical Affairs and Research, Edward Via College of Osteopathic Medicine, Monroe, LA 71203, USA.
Int J Mol Sci. 2025 May 26;26(11):5112. doi: 10.3390/ijms26115112.
Emergent cancer drug resistance and further metastasis can mainly be attributed to altered expression levels and functional activities of multiple genes of cancer cells under chemotherapy. In response to challenge with anticancer drugs, enhanced ceramide glycosylation catalyzed by glucosylceramide synthase (GCS) confers drug resistance and enrichment with cancer stem cells. p53 mutations, which gain function in tumor progression, are prevalently extant in ovarian cancers. Via integrated gene expression assessments, we characterized GCS-responsive genes in ovarian cancer cells treated with dactinomycin. NCI/ADR-RES cells dominantly expressed a p53 mutant (7 aa deleted in exon-5) and displayed anti-apoptosis; however, silencing GCS expression rendered these cells sensitive to dactinomycin-induced apoptosis. Microarray analyses of NCI/ADR-RES and its GCS transfected sublines found that elevated GCS expression or ceramide glycosylation was associated with altered expression of 41 genes, notably coding for ABCB1, FGF2, ALDH1A3, apolipoprotein E, laminin 2, chemokine ligands, and IL6, with cellular resistance to induced apoptosis and enrichment with cancer stem cells, promoting cancer progression. These findings were further corroborated through integrated genomic analyses of ovarian cancer from The Cancer Genome Atlas (TCGA) and cancer resistance to platinum-based chemotherapy. Altogether, our present study indicates that altered ceramide glycosylation can modulate expression of these GCS-responsive genes and alter cancer cell attributes under chemotherapy.
癌症的紧急耐药性及进一步转移主要归因于化疗作用下癌细胞多个基因的表达水平和功能活性发生改变。在应对抗癌药物的挑战时，由葡萄糖神经酰胺合酶（GCS）催化的神经酰胺糖基化增强赋予了癌细胞耐药性并使其富集癌症干细胞。p53突变在肿瘤进展中获得功能，在卵巢癌中普遍存在。通过综合基因表达评估，我们对用放线菌素处理的卵巢癌细胞中的GCS反应基因进行了表征。NCI/ADR-RES细胞主要表达一种p53突变体（外显子5缺失7个氨基酸）并表现出抗凋亡能力；然而，沉默GCS表达使这些细胞对放线菌素诱导的凋亡敏感。对NCI/ADR-RES及其GCS转染亚系进行微阵列分析发现，GCS表达升高或神经酰胺糖基化与41个基因的表达改变有关，特别是编码ABCB1、FGF2、ALDH1A3、载脂蛋白E、层粘连蛋白2、趋化因子配体和IL6的基因，这与细胞对诱导凋亡的抗性以及癌症干细胞的富集有关，促进了癌症进展。通过对癌症基因组图谱（TCGA）中的卵巢癌以及对铂类化疗的耐药性进行综合基因组分析，进一步证实了这些发现。总之，我们目前的研究表明，神经酰胺糖基化的改变可调节这些GCS反应基因的表达，并在化疗作用下改变癌细胞的特性。
