Role of neutral ceramidase in colon cancer.
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 β-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.-García-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.
Department of Medicine, Stony Brook University, New York, USA.|Stony Brook Cancer Center, Stony Brook University, Stony Brook, New York, USA.
Mónica
M
García-Barros
Department of Medicine, Stony Brook University, New York, USA.|Stony Brook Cancer Center, Stony Brook University, Stony Brook, New York, USA.
Nicolas
N
Coant
Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA.|Research Institute for Cancer Prevention and Pathologic Diagnosis at Tokyo Leon Clinics, Nagoya, Japan.
Toshihiko
T
Kawamori
Department of Medicine, Stony Brook University, New York, USA.|Stony Brook Cancer Center, Stony Brook University, Stony Brook, New York, USA.
Masayuki
M
Wada
Department of Medicine, Stony Brook University, New York, USA.|Stony Brook Cancer Center, Stony Brook University, Stony Brook, New York, USA.|Northport Veterans Affairs Medical Center, Northport, New York, USA.
Ashley J
AJ
Snider
Department of Medicine, Stony Brook University, New York, USA.|Stony Brook Cancer Center, Stony Brook University, Stony Brook, New York, USA.
Jean-Philip
JP
Truman
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA.
Bill X
BX
Wu
Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA.
Hideki
H
Furuya
Department of Medicine, Stony Brook University, New York, USA.|Stony Brook Cancer Center, Stony Brook University, Stony Brook, New York, USA.
Christopher J
CJ
Clarke
Department of Medicine, Stony Brook University, New York, USA.
Agnieszka B
AB
Bialkowska
Department of Medicine, Stony Brook University, New York, USA.
Amr
A
Ghaleb
Department of Medicine, Stony Brook University, New York, USA.
Vincent W
VW
Yang
Department of Medicine, Stony Brook University, New York, USA.|Stony Brook Cancer Center, Stony Brook University, Stony Brook, New York, USA.|Northport Veterans Affairs Medical Center, Northport, New York, USA.
Lina M
LM
Obeid
Department of Medicine, Stony Brook University, New York, USA; yusuf.hannun@stonybrookmedicine.edu.|Stony Brook Cancer Center, Stony Brook University, Stony Brook, New York, USA.|Department of Biochemistry, Stony Brook University, Stony Brook, New York, USA.|Department of Pharmacology, Stony Brook University, Stony Brook, New York, USA; and.|Department of Pathology, Stony Brook University, Stony Brook, New York, USA.
Yusuf A
YA
Hannun
D000818:Animals; D002518:Ceramides / Q000378:metabolism*; D003106:Colon / Q000378:metabolism; D003110:Colonic Neoplasms / Q000201:enzymology*; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology*; D008297:Male; D018345:Mice, Knockout; D055576:Neutral Ceramidase / Q000378:metabolism*; D013107:Sphingolipids / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
D002518:Ceramides; D013107:Sphingolipids; D051176:beta Catenin; D055576:Neutral Ceramidase
aberrant crypt foci; apoptosis; azoxymethane; sphingolipids ceramide