Chemosensitivity of human colon cancer cells is influenced by a p53-dependent enhancement of ceramide synthase 5 and induction of autophagy.

Abstract

Resistance against chemotherapy is a life-threatening complication in colon cancer therapy. To increase response rate, new additional targets that contribute to chemoresistance are still needed to be explored. Ceramides, which belong to the group of sphingolipids, are well-known regulators of cell death and survival, respectively. Here, we show that in human wild-type (wt) p53 HCT-116 colon cancer cells treatment with oxaliplatin or 5-fluorouracil (5-FU) leads to a strong increase in ceramide synthase 5 (CerS5) expression and C16:0-ceramide levels, which was not shown in HCT-116 lacking p53 expression (HCT-116 p53-/-). The increase in CerS5 expression occurs by stabilizing CerS5 mRNA at the 3'-UTR. By contrast, in the p53-deficient cells CerS2 expression and CerS2-related C24:0- and C24:1-ceramide levels were elevated which is possibly related to enhanced polyadenylation of the CerS2 transcript in these cells. Stable knockdown of CerS5 expression using CerS5-targeting shRNA led to an increased sensitivity of HCT-116 p53wt cells, but not of p53-/- cells, to oxaliplatin and 5-FU. Enhanced sensitivity was accompanied by an inhibition of autophagy and inhibition of mitochondrial respiration in these cells. However, knockdown of CerS2 had no significant effects on chemosensitivity of both cell lines. In conclusion, in p53wt colon cancer cells chemosensitivity against oxaliplatin or 5-FU could be enhanced by downregulation of CerS5 expression leading to reduced autophagy and mitochondrial respiration.

• Authors: Sebastian Brachtendorf, Ruth Anna Wanger, Kerstin Birod, Dominique Thomas, Sandra Trautmann, Marthe-Susanna Wegner, Dominik C Fuhrmann, Bernhard Brüne, Gerd Geisslinger, Sabine Grösch
• Journal: Biochimica et biophysica acta. Molecular and cell biology of lipids (Biochim Biophys Acta Mol Cell Biol Lipids) Vol. 1863 Issue 10 Pg. 1214-1227 (10 2018) ISSN: 1879-2618 [Electronic] Netherlands
• PMID: 30059758 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Sphingolipids
• Tumor Suppressor Protein p53
• Oxaliplatin
• CERS5 protein, human
• Sphingosine N-Acyltransferase
• Fluorouracil

Topics

• Autophagy (drug effects)
• Colonic Neoplasms (drug therapy, genetics, metabolism, pathology)
• Down-Regulation (drug effects)
• Fluorouracil (pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• HCT116 Cells
• Humans
• Oxaliplatin (pharmacology)
• Sphingolipids (metabolism)
• Sphingosine N-Acyltransferase (metabolism)
• Transcription, Genetic (drug effects)
• Tumor Suppressor Protein p53 (metabolism)