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

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 C_16:0-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 C_24:0- and C_24:1-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 p53^wt 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 p53^wt colon cancer cells chemosensitivity against oxaliplatin or 5-FU could be enhanced by downregulation of CerS5 expression leading to reduced autophagy and mitochondrial respiration.

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