Inhibition of Ceramide Glycosylation Enhances Cisplatin Sensitivity in Cholangiocarcinoma by Limiting the Activation of the ERK Signaling Pathway.

Piyasiri Chueakwon,Peeranat Jatooratthawichot,Krajang Talabnin,Chutima Talabnin,James R Ketudat Cairns

doi:10.3390/life12030351

Piyasiri Chueakwon, Peeranat Jatooratthawichot + Show 3 more

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https://doi.org/10.3390/life12030351

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Journal: Life	Publication Date: Feb 28, 2022
Citations: 5	License type: CC BY 4.0

Affiliation: Suranaree University of Technology

Abstract

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.

Highlights

Published: 28 February 2022Cholangiocarcinoma (CCA) is one of the most common aggressive malignancies of the bile duct epithelium, with an increasing worldwide incidence, in SoutheastAsia and Eastern Europe [1]
The expression level of glucosylceramide synthase (GCS) was higher in the CCA tumor tissues than the other glucocerebrosidase (GBA1, glucocerebrosidase 2 (GBA2), and GBA3)
Both the GCS and the glucocerebrosidase 1 (GBA1) expression levels were significantly upregulated in CCA tumor tissues (Figure 1B,C), whereas the GBA2 and GBA3 were downregulated compared with matched paired non-tumor CCA tissues (Figure 1D,E)

Summary

Introduction

Cholangiocarcinoma (CCA) is one of the most common aggressive malignancies of the bile duct epithelium, with an increasing worldwide incidence, in Southeast. Inoperable advanced stage, and resistance to chemotherapy remain major obstacles to CCA treatment [2,3]. Conventional chemotherapeutic agents—including 5-fluorouracil, cisplatin, leucovorin, mitomycin, gemcitabine, and cisplatin—have been used either alone or in combination with a response rate ranging between 20 and 30% [4,5]. The current first-line chemotherapeutic regimen used in CCA treatment is a combination of gemcitabine and cisplatin [6]. The effectiveness of this regimen has been modest as the 5-year survival of 564 CCA patients between 1973 and 2004 was 18% [7,8]. A new treatment option for CCA is urgently needed

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