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Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays
Published on: September 19, 2018
Effects of tyroserleutide on gene expression of calmodulin and PI3K in hepatocellular carcinoma
1Department of Immunology, Tianjin Medical University, Tianjin 300070, China.
Abstract:
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.
Insights
Tyroserleutide (YSL) inhibits hepatocellular carcinoma by downregulating calmodulin (CaM) and phosphatidylinositol 3 kinase (PI3K) pathways. This tripeptide compound affects CaM protein and PI3K activity, suggesting a novel anti-tumor mechanism.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Hepatocellular carcinoma (HCC) is a major global health concern.
- The Ca(2+)/calmodulin (CaM) pathway and phosphatidylinositol 3 kinase (PI3K) signaling are implicated in tumor development.
- Tyroserleutide (YSL), a tripeptide, has shown prior inhibitory effects on HCC.
Purpose of the Study:
- To investigate the anti-tumor mechanism of YSL in human hepatocellular carcinoma BEL-7402 xenograft tumors.
- To determine the effects of YSL on CaM and PI3K pathway components.
Main Methods:
- Studied YSL's impact on CaM protein expression and mRNA levels.
- Assessed PI3K activity and the expression of PI3K regulatory (p85) and catalytic (p110alpha, p110gamma) subunits.
- Utilized human hepatocellular carcinoma BEL-7402 xenograft tumor models in nude mice.
Main Results:
- YSL significantly decreased CaM mRNA levels and protein expression.
- YSL inhibited PI3K activity.
- YSL reduced the mRNA and protein expression of the PI3K regulatory subunit p85 and the mRNA levels of PI3K catalytic subunits p110alpha and p110gamma.
Conclusions:
- YSL exerts anti-tumor effects in HCC by downregulating CaM and PI3K signaling pathways.
- YSL may overcome dysfunctional PI3K activity in tumors by influencing key signal transduction components.
- These findings suggest YSL as a potential therapeutic agent for hepatocellular carcinoma.
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