TY - JOUR
T1 - Role of neutral ceramidase in colon cancer
AU - García-Barros, Mónica
AU - Coant, Nicolas
AU - Kawamori, Toshihiko
AU - Wada, Masayuki
AU - Snider, Ashley J.
AU - Truman, Jean Philip
AU - Wu, Bill X.
AU - Furuya, Hideki
AU - Clarke, Christopher J.
AU - Bialkowska, Agnieszka B.
AU - Ghaleb, Amr
AU - Yang, Vincent W.
AU - Obeid, Lina M.
AU - Hannun, Yusuf A.
N1 - Publisher Copyright:
© 2016 FASEB.
PY - 2016/12
Y1 - 2016/12
N2 - 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 resultedinloss 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 fromtumor formation. Taken together, these studies show that nCDase is pivotal for regulating initiation and development of colon cancer, and thesedata suggest that this enzyme is a suitable and novel target for colon cancer therapy.
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 resultedinloss 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 fromtumor formation. Taken together, these studies show that nCDase is pivotal for regulating initiation and development of colon cancer, and thesedata suggest that this enzyme is a suitable and novel target for colon cancer therapy.
KW - Aberrant crypt foci
KW - Apoptosis
KW - Azoxymethane
KW - Sphingolipids ceramide
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UR - http://www.scopus.com/inward/citedby.url?scp=85002213807&partnerID=8YFLogxK
U2 - 10.1096/fj.201600611R
DO - 10.1096/fj.201600611R
M3 - Article
C2 - 27609772
AN - SCOPUS:85002213807
VL - 30
SP - 4159
EP - 4171
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 12
ER -