PMID- 27609772 OWN - NLM STAT- MEDLINE DCOM- 20170921 LR - 20181113 IS - 1530-6860 (Electronic) IS - 0892-6638 (Print) IS - 0892-6638 (Linking) VI - 30 IP - 12 DP - 2016 Dec TI - Role of neutral ceramidase in colon cancer. PG - 4159-4171 AB - Alterations in sphingolipid metabolism, especially ceramide and sphingosine 1-phosphate, have been linked to colon cancer, suggesting that enzymes of sphingolipid metabolism may emerge as novel regulators and targets in colon cancer. Neutral ceramidase (nCDase), a key enzyme in sphingolipid metabolism that hydrolyzes ceramide into sphingosine, is highly expressed in the intestine; however, its role in colon cancer has not been defined. Here we show that molecular and pharmacological inhibition of nCDase in colon cancer cells increases ceramide, and this is accompanied by decreased cell survival and increased apoptosis and autophagy, with minimal effects on noncancerous cells. Inhibition of nCDase resulted in loss of beta-catenin and inhibition of ERK, components of pathways relevant for colon cancer development. Furthermore, inhibition of nCDase in a xenograft model delayed tumor growth and increased ceramide while decreasing proliferation. It is noteworthy that mice lacking nCDase treated with azoxymethane were protected from tumor formation. Taken together, these studies show that nCDase is pivotal for regulating initiation and development of colon cancer, and these data suggest that this enzyme is a suitable and novel target for colon cancer therapy.-Garcia-Barros, M., Coant, N., Kawamori, T., Wada, M., Snider, A. J., Truman, J.-P., Wu, B. X., Furuya, H., Clarke, C. J., Bialkowska, A. B., Ghaleb, A., Yang, V. W., Obeid, L. M., Hannun, Y. A. Role of neutral ceramidase in colon cancer. CI - (c) FASEB. FAU - Garcia-Barros, Monica AU - Garcia-Barros M AD - Department of Medicine, Stony Brook University, New York, USA. AD - Stony Brook Cancer Center, Stony Brook University, Stony Brook, New York, USA. FAU - Coant, Nicolas AU - Coant N AD - Department of Medicine, Stony Brook University, New York, USA. AD - Stony Brook Cancer Center, Stony Brook University, Stony Brook, New York, USA. FAU - Kawamori, Toshihiko AU - Kawamori T AD - Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA. AD - Research Institute for Cancer Prevention and Pathologic Diagnosis at Tokyo Leon Clinics, Nagoya, Japan. FAU - Wada, Masayuki AU - Wada M AD - Department of Medicine, Stony Brook University, New York, USA. AD - Stony Brook Cancer Center, Stony Brook University, Stony Brook, New York, USA. FAU - Snider, Ashley J AU - Snider AJ AD - Department of Medicine, Stony Brook University, New York, USA. AD - Stony Brook Cancer Center, Stony Brook University, Stony Brook, New York, USA. AD - Northport Veterans Affairs Medical Center, Northport, New York, USA. FAU - Truman, Jean-Philip AU - Truman JP AD - Department of Medicine, Stony Brook University, New York, USA. AD - Stony Brook Cancer Center, Stony Brook University, Stony Brook, New York, USA. FAU - Wu, Bill X AU - Wu BX AD - Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA. FAU - Furuya, Hideki AU - Furuya H AD - Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA. FAU - Clarke, Christopher J AU - Clarke CJ AD - Department of Medicine, Stony Brook University, New York, USA. AD - Stony Brook Cancer Center, Stony Brook University, Stony Brook, New York, USA. FAU - Bialkowska, Agnieszka B AU - Bialkowska AB AD - Department of Medicine, Stony Brook University, New York, USA. FAU - Ghaleb, Amr AU - Ghaleb A AD - Department of Medicine, Stony Brook University, New York, USA. FAU - Yang, Vincent W AU - Yang VW AD - Department of Medicine, Stony Brook University, New York, USA. FAU - Obeid, Lina M AU - Obeid LM AD - Department of Medicine, Stony Brook University, New York, USA. AD - Stony Brook Cancer Center, Stony Brook University, Stony Brook, New York, USA. AD - Northport Veterans Affairs Medical Center, Northport, New York, USA. FAU - Hannun, Yusuf A AU - Hannun YA AD - Department of Medicine, Stony Brook University, New York, USA; yusuf.hannun@stonybrookmedicine.edu. AD - Stony Brook Cancer Center, Stony Brook University, Stony Brook, New York, USA. AD - Department of Biochemistry, Stony Brook University, Stony Brook, New York, USA. AD - Department of Pharmacology, Stony Brook University, Stony Brook, New York, USA; and. AD - Department of Pathology, Stony Brook University, Stony Brook, New York, USA. LA - eng GR - P01 CA097132/CA/NCI NIH HHS/United States GR - R01 CA172113/CA/NCI NIH HHS/United States GR - R01 CA172517/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20160908 PL - United States TA - FASEB J JT - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JID - 8804484 RN - 0 (Ceramides) RN - 0 (Sphingolipids) RN - 0 (beta Catenin) RN - EC 3.5.1.23 (Neutral Ceramidase) SB - IM MH - Animals MH - Ceramides/*metabolism MH - Colon/metabolism MH - Colonic Neoplasms/*enzymology MH - Humans MH - Lipid Metabolism/*physiology MH - Male MH - Mice, Knockout MH - Neutral Ceramidase/*metabolism MH - Sphingolipids/metabolism MH - beta Catenin/metabolism PMC - PMC5102116 OTO - NOTNLM OT - aberrant crypt foci OT - apoptosis OT - azoxymethane OT - sphingolipids ceramide EDAT- 2016/09/10 06:00 MHDA- 2017/09/22 06:00 PMCR- 2017/12/01 CRDT- 2016/09/10 06:00 PHST- 2016/05/23 00:00 [received] PHST- 2016/08/22 00:00 [accepted] PHST- 2016/09/10 06:00 [pubmed] PHST- 2017/09/22 06:00 [medline] PHST- 2016/09/10 06:00 [entrez] PHST- 2017/12/01 00:00 [pmc-release] AID - fj.201600611R [pii] AID - FJ_201600611R [pii] AID - 10.1096/fj.201600611R [doi] PST - ppublish SO - FASEB J. 2016 Dec;30(12):4159-4171. doi: 10.1096/fj.201600611R. Epub 2016 Sep 8.