Chueakwon Piyasiri, Jatooratthawichot Peeranat, Talabnin Krajang, Ketudat Cairns James R, Talabnin Chutima
School of Chemistry, Institute of Science, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand.
School of Pathology, Institute of Medicine, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand.
Life (Basel). 2022 Feb 28;12(3):351. doi: 10.3390/life12030351.
Cholangiocarcinoma (CCA) is an aggressive tumor of the biliary epithelium with poor survival that shows limited response to conventional chemotherapy. Increased expression of glucosylceramide synthase (GCS) contributes to drug resistance and the progression of various cancers; the expression profiles of GCS (UGCG) and the genes for glucocerebrosidases 1, 2, and 3 (GBA1, GBA2, and GBA3) were therefore studied in CCA. The biological functions of GCS for cell proliferation and cisplatin sensitivity in CCA were explored. GCS expression was higher in CCA tumor tissues than that of GBA1, GBA2, and GBA3. Verification of GCS expression in 29 paired frozen CCA tissues showed that 8 of 29 cases (27.6%) had high GCS expression. The expression of GCS and GBA2 was induced in CCA cell lines following low-dose cisplatin treatment. Suppression of GCS by either palmitoylamino-3-morpholino-1-propanol (PPMP), GCS knockdown or a combination of the two resulted in reduced cell proliferation. These treatments enhanced the effect of cisplatin-induced CCA cell death, increased the expression of apoptotic proteins and reduced phosphorylation of ERK upon cisplatin treatment. Taken together, inhibition of the GCS increased cisplatin-induced CCA apoptosis via the inhibition of the ERK signaling pathway. Thus, targeting GCS might be a strategy for CCA treatment.
胆管癌（CCA）是一种侵袭性的胆管上皮肿瘤，生存率低，对传统化疗反应有限。葡萄糖神经酰胺合酶（GCS）表达增加与多种癌症的耐药性及进展有关；因此，研究了CCA中GCS（UGCG）以及葡萄糖脑苷脂酶1、2和3（GBA1、GBA2和GBA3）基因的表达谱。探讨了GCS在CCA中对细胞增殖和顺铂敏感性的生物学功能。CCA肿瘤组织中GCS的表达高于GBA1、GBA2和GBA3。对29对冷冻CCA组织中GCS表达的验证表明，29例中有8例（27.6%）GCS高表达。低剂量顺铂处理后，CCA细胞系中GCS和GBA2的表达被诱导。棕榈酰氨基-3-吗啉代-1-丙醇（PPMP）、GCS基因敲低或二者联合抑制GCS均导致细胞增殖减少。这些处理增强了顺铂诱导的CCA细胞死亡效应，增加了凋亡蛋白的表达，并降低了顺铂处理后ERK的磷酸化。综上所述，抑制GCS通过抑制ERK信号通路增加顺铂诱导的CCA细胞凋亡。因此，靶向GCS可能是一种治疗CCA的策略。
