Acid sphingomyelinase is induced by butyrate but does not initiate the anticancer effect of butyrate in HT29 and HepG2 cells.
Butyric acid and sphingomyelin (SM) affect colonic tumorigenesis. We examined the potential link between butyrate stimulation and SM metabolism in colonic and hepatic cancer cell lines. After incubating HT29 and HepG2 cells with butyrate and other short-chain fatty acids, we found that butyrate increased acid but not neutral or alkaline sphingomyelinase (SMase) activity by 10- to 20-fold. The effects occurred after 16 h of incubation and were associated with reduced SM and phosphatidylcholine contents and increased ceramide levels. Northern blotting showed increased acid SMase mRNA levels in these cells after butyrate stimulation. Propionate was less potent, and acetate had no effect. No similar changes of acid phosphatase could be identified. At concentrations that increased acid SMase expression, butyrate inhibited cell proliferation, activated caspase 3, and induced apoptosis. However, the antiproliferative and apoptotic effects of butyrate preceded the changes of acid SMase and were not affected by knocking down acid SMase expression by small, interfering RNA. In addition, butyrate-induced acid SMase expression was not affected by blocking the caspase pathway. In conclusion, butyrate regulates SM metabolism by stimulating acid SMase expression in colon and liver cancer cells, but the increased acid SMase is not a critical mechanism for initiating the anticancer effects of butyrate.
Wu
Jun
J
Gastroenterology Laboratory, Biomedical Center B11, Lund University, S-221 84 Lund, Sweden.
Cheng
Yajun
Y
Jönsson
Bo A G
BA
Nilsson
Ake
A
Duan
Rui-Dong
RD
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002087:Butyrates / Q000494:pharmacology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002518:Ceramides / Q000032:analysis; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000473:pathology; D010713:Phosphatidylcholines / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering / Q000494:pharmacology; D013108:Sphingomyelin Phosphodiesterase / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D013109:Sphingomyelins / Q000032:analysis / Q000378:metabolism
D000970:Antineoplastic Agents; D002087:Butyrates; D002518:Ceramides; D010713:Phosphatidylcholines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013109:Sphingomyelins; D013108:Sphingomyelin Phosphodiesterase; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases