Targeting the sphingolipid metabolism to defeat pancreatic cancer cell resistance to the chemotherapeutic gemcitabine drug

Guillermet-Guibert, Julie, Davenne, Lise, Pchejetski, Dmitry, Saint-Laurent, Nathalie, Brizuela, Leyre, Guilbeau-Frugier, Céline, Delisle, Marie-Bernadette, Cuvillier, Olivier, Susini, Christiane and Bousquet, Corinne (2009) Targeting the sphingolipid metabolism to defeat pancreatic cancer cell resistance to the chemotherapeutic gemcitabine drug. Molecular Cancer Therapeutics, 8 (4). pp. 809-20. ISSN 1535-7163

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Abstract

Defeating pancreatic cancer resistance to the chemotherapeutic drug gemcitabine remains a challenge to treat this deadly cancer. Targeting the sphingolipid metabolism for improving tumor chemosensitivity has recently emerged as a promising strategy. The fine balance between intracellular levels of the prosurvival sphingosine-1-phosphate (S1P) and the proapoptotic ceramide sphingolipids determines cell fate. Among enzymes that control this metabolism, sphingosine kinase-1 (SphK1), a tumor-associated protein overexpressed in many cancers, favors survival through S1P production, and inhibitors of SphK1 are used in ongoing clinical trials to sensitize epithelial ovarian and prostate cancer cells to various chemotherapeutic drugs. We here report that the cellular ceramide/S1P ratio is a critical biosensor for predicting pancreatic cancer cell sensitivity to gemcitabine. A low level of the ceramide/S1P ratio, associated with a high SphK1 activity, correlates with a robust intrinsic pancreatic cancer cell chemoresistance toward gemcitabine. Strikingly, increasing the ceramide/S1P ratio, by using pharmacologic (SphK1 inhibitor or ceramide analogue) or small interfering RNA-based approaches to up-regulate intracellular ceramide levels or reduce SphK1 activity, sensitized pancreatic cancer cells to gemcitabine. Conversely, decreasing the ceramide/S1P ratio, by up-regulating SphK1 activity, promoted gemcitabine resistance in these cells. Development of novel pharmacologic strategies targeting the sphingolipid metabolism might therefore represent an interesting promising approach, when combined with gemcitabine, to defeat pancreatic cancer chemoresistance to this drug.

Item Type:	Article
Uncontrolled Keywords:	blotting, western,cell proliferation,cell survival,ceramides,deoxycytidine,drug resistance, neoplasm,enzyme inhibitors,humans,lysophospholipids,pancreatic neoplasms,phosphotransferases (alcohol group acceptor),rna, messenger,reverse transcriptase polymerase chain reaction,ribonucleotide reductases,sphingosine,tumor cells, cultured,sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User:	Pure Connector
Date Deposited:	16 Dec 2014 10:06
Last Modified:	21 Oct 2022 00:23
URI:	https://ueaeprints.uea.ac.uk/id/eprint/51540
DOI:	10.1158/1535-7163.MCT-08-1096

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