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Raf and PI3K are the molecular targets for the anti-metastatic effect of luteolin
Ho Young Kim1, Sung Keun Jung, Sanguine Byun
1WCU Major in Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul, 151-921, Republic of Korea; Department of Agricultural Biotechnology, Seoul National University, Seoul, 151-921, Republic of Korea.
Abstract:
Metastases are the primary cause of human cancer deaths. Luteolin, a naturally occurring phytochemical, has chemopreventive and/or anticancer properties in several cancer cell lines. However, anti-metastatic effects of luteolin in vivo and the underlying molecular mechanisms and target(s) remain unknown. Luteolin suppresses matrix metalloproteinase (MMP)-2 and -9 activities and invasion in murine colorectal cancer CT-26 cells. Western blot and kinase assay data revealed that luteolin inhibited Raf and phosphatidylinositol 3-kinase (PI3K) activities and subsequently attenuated phosphorylation of MEK and Akt. A pull-down assay indicated that luteolin non-competitively bound with ATP to suppress Raf activity and competitively bound with ATP to inhibit PI3K activity. GW5074, a Raf inhibitor, and LY294002, a PI3K inhibitor, inhibited MMP-2 and -9 activities and invasion in CT-26 cells. An in vivo mouse study showed that oral administration (10 or 50 mg/kg) of luteolin significantly inhibited tumor nodules and tumor volume of lung metastasis induced by intravenous injection of CT-26 cells. Luteolin also inhibited MMP-9 expression and activity in CT-26-induced mouse lung tissue. These results suggest that luteolin may have considerable potential for development as an anti-metastatic agent.
Insights
Luteolin, a natural compound, effectively inhibited cancer metastasis in mice by targeting key signaling pathways. This phytochemical shows promise as a novel anti-metastatic agent for cancer treatment.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Metastasis is the leading cause of cancer mortality.
- Luteolin, a phytochemical, exhibits anticancer properties in vitro.
- The in vivo anti-metastatic effects and mechanisms of luteolin are not well understood.
Purpose of the Study:
- To investigate the anti-metastatic effects of luteolin in vivo.
- To elucidate the molecular mechanisms underlying luteolin's anti-metastatic action.
- To identify potential molecular targets of luteolin in cancer metastasis.
Main Methods:
- In vitro assays using murine colorectal cancer CT-26 cells to assess MMP-2 and MMP-9 activity and invasion.
- Western blot and kinase assays to evaluate Raf, PI3K, MEK, and Akt signaling.
- In vivo mouse model of lung metastasis induced by CT-26 cells.
- Oral administration of luteolin in mice.
Main Results:
- Luteolin suppressed MMP-2 and MMP-9 activities and invasion in CT-26 cells.
- Luteolin inhibited Raf and PI3K activities, leading to decreased MEK and Akt phosphorylation.
- Luteolin non-competitively bound ATP to inhibit Raf and competitively bound ATP to inhibit PI3K.
- In vivo, luteolin administration significantly reduced lung metastasis nodules and tumor volume.
- Luteolin inhibited MMP-9 expression and activity in mouse lung tissue.
Conclusions:
- Luteolin demonstrates significant in vivo anti-metastatic potential against colorectal cancer lung metastasis.
- The anti-metastatic effects of luteolin are mediated through the inhibition of Raf/MEK and PI3K/Akt signaling pathways.
- Luteolin warrants further investigation as a potential therapeutic agent for preventing cancer metastasis.
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