Effects of tyroserleutide on gene expression of calmodulin and PI3K in hepatocellular carcinoma.
Tyroserleutide (YSL) is a tripeptide compound that has exhibited inhibitory effects on hepatocellular carcinoma in our previous research. The mechanism of this antitumor activity involves the second messenger, Ca(2+). Ca(2+) influences cell function through the Ca(2+)/calmodulin (CaM) pathway, and abnormality of the Ca(2+)/CaM system correlates closely with the occurrence of tumors. In addition, CaM associates with phosphatidylinositol 3 kinase (PI3K), thereby enhancing the activity of PI3K, which promotes cell proliferation. In order to investigate its anti-tumor mechanism, we studied the effects of YSL on CaM protein expression and mRNA level, PI3K activity, PI3K regulatory subunit p85 protein expression and mRNA level, and the mRNA level of PI3K catalytic subunits p110alpha and p110gamma in human hepatocellular carcinoma BEL-7402 xenograft tumors in nude mice. Our results showed that YSL decreased the mRNA level and protein expression of CaM, inhibited the activity of PI3K, and reduced the mRNA level and protein expression of the PI3K regulatory subunit p85 and mRNA level of PI3K catalytic subunits p110alpha and p110gamma. Accordingly, it is suggestive that the anti-tumor effects of YSL may be mediated by down regulation of CaM and PI3K subunits p85 and p110, influencing the signal transduction pathway in the tumor cells and perhaps overcoming the dysfunctional PI3K activity in tumors.
Zhao
Lan
L
Department of Immunology, Tianjin Medical University, Tianjin 300070, China.
Zhao
Qian
Q
Lu
Rong
R
Fu
Zheng
Z
Zhu
Zhifeng
Z
Jia
Jing
J
Wang
Song
S
Shi
Linxi
L
Jian
Xu
X
Yao
Zhi
Z
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D020013:Calcium Signaling / Q000187:drug effects; D002147:Calmodulin / Q000096:biosynthesis* / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D045744:Cell Line, Tumor / Q000637:transplantation; D058534:Class I Phosphatidylinositol 3-Kinases; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D013047:Specific Pathogen-Free Organisms; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D002147:Calmodulin; D009363:Neoplasm Proteins; D009842:Oligopeptides; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C497132:PIK3CB protein, human; C484773:H-Tyr-Ser-Leu-OH