Inhibitory effect of S-adenosylmethionine on the growth of human gastric cancer cells in vivo and in vitro.
OBJECTIVE
S-adenosylmethionine (SAM), the most important methyl donor in human body, is generally used to treat cholestasis in clinic. In recent years, SAM has been found to have inhibitory effects on breast cancer, liver cancer and colon carcinoma. This study was to investigate the inhibitory effects of SAM on human gastric cancer cells in vivo and in vitro, and the antitumor mechanisms.


METHODS
The effects of SAM on the proliferation of gastric cancer SGC-7901 and MKN-45 cells were determined by MTT assay. After SGC-7901 and MKN-45 cells were treated with 0, 2, and 4 mmol/L SAM for 72 h, the expression and methylation of c-myc and urokinase type plasminogen activator (uPA) were detected by reverse transcription-polymerase chain reaction (RT-PCR) and methylation-specific PCR (MSP). Tumor xenografts were established by injecting SGC-7901 cells subcutaneously in BALB/c nude mice. The mice were randomized into low concentration group [192 µmol/(kg · day)], high concentration group [768 µmol/(kg · day)], and control group [normal saline (NS)], and received peritoneal injection of relative reagents for 15 days. The tumor size was measured, the protein and mRNA expression of c-myc and uPA were detected by immunohistochemistry and RT-PCR, and the methylation of c-myc and uPA genes was detected by MSP.


RESULTS
SAM inhibited the growth of SGC-7901 and MKN-45 cells obviously and the effects were enhanced with the increase of SAM concentration and treatment time. The mRNA expression of c-myc and uPA in SGC-7901 cells and that of uPA in MKN-45 cells significantly decreased. The c-myc and uPA genes in SGC-7901 cells and uPA gene in MKN-45 cells were partly or completely methylated after SAM treatment. The tumor volume was significantly lower in low concentration group [(618.51 ± 149.27) mm³] and high concentration group [(444.32 ± 118.51) mm³] than in control group [(1018.22 ± 223.07) mm³] (both P < 0.01). The inhibitory rates of tumor growth were 39.26% in low concentration group and 56.36% in high concentration group. The protein and mRNA expressions of c-myc and uPA were remarkably reduced (all P < 0.01), and the hypomethylation of c-myc and uPA genes were reversed after SAM treatment.


CONCLUSIONS
SAM can inhibit the growth of human gastric cancer cells both in vivo and in vitro. The mechanism may be that SAM can reverse the hypomethylation of c-myc and uPA genes, reduce their expression, and then inhibit tumor growth.
Zhao
Ye
Y
Department of Gastroenterology, the First Affiliated Hospital of Zhengzhou University, Key-Disciplines Laboratory Clinical-Medicine, Zhengzhou, Henan 450052, P. R. China.
Li
Jian-Sheng
JS
Guo
Ming-Zhou
MZ
Feng
Bai-Sui
BS
Zhang
Jin-Ping
JP
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019175:DNA Methylation; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology*; D047368:Tumor Burden / Q000187:drug effects; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D012436:S-Adenosylmethionine; D014568:Urokinase-Type Plasminogen Activator