Ras/MAP kinase pathways are involved in Ras specific apoptosis induced by sodium butyrate.
Histone deacetylase inhibitors such as TSA, SAHA, and NaBu etc. are prospective cancer therapeutics of growing interest. Here, we demonstrated that oncogenic ras-transformed rat liver epithelial (WB-ras) cells were specifically undergone apoptosis by 48 h treatment of NaBu. During this, inhibition of ras proteins, especially farnesylated form of ras, and down-regulation of ERK1/2 were observed, which suggest ras/raf/MEK/ERK down-regulation, while p38 MAP kinase was maintained up-regulated. In addition, up-regulation of pro-apoptotic proteins such as p53 and p21CIP1/WAF1, and down-regulation of cell cycle regulator/anti-apoptotic proteins such as cdk2, -4 and phosphorylated Akt were observed concurrently with an increase in apoptotic cell portion. A phosphatase inhibitor, sodium orthovanadate (SOV), efficiently blocked apoptosis and restored responsible proteins for each phenomenon including ERK1/2 while SB203580, a specific p38 MAP kinase inhibitor, showed minor effect on them. Thus, ras/ERK signaling pathway can be considered in chemotherapeutic strategies of NaBu regardless of its inhibitory action on histone deacetylase.
Department of Veterinary Public Health, College of Veterinary Medicine, Seoul National University, Seoul 151-742, South Korea.
Ji-Won
JW
Jung
Sung-Dae
SD
Cho
Nam-Shik
NS
Ahn
Se-Ran
SR
Yang
Joon-Suk
JS
Park
Eun-Hye
EH
Jo
Jae-Woong
JW
Hwang
Ji-Youn
JY
Jung
Sung-Hoon
SH
Kim
Kyung-Sun
KS
Kang
Yong-Soon
YS
Lee
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002087:Butyrates / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D007093:Imidazoles / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D013379:Substrate Specificity; D018631:ras Proteins / Q000378:metabolism*
D002087:Butyrates; D018797:Cell Cycle Proteins; D056572:Histone Deacetylase Inhibitors; D007093:Imidazoles; D011725:Pyridines; D020928:Mitogen-Activated Protein Kinases; D010744:Phosphoric Monoester Hydrolases; D018631:ras Proteins; C093642:SB 203580