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Phellinus linteus suppresses growth, angiogenesis and invasive behaviour of breast cancer cells through the inhibition of AKT signalling.

Sliva D, Jedinak A, Kawasaki J, Harvey K, Slivova V - Br. J. Cancer (2008)

Bottom Line: The growth inhibition of MDA-MB-231 cells is mediated by the cell cycle arrest at S phase through the upregulation of p27(Kip1) expression.In addition, PL markedly inhibited the early event in angiogenesis, capillary morphogenesis of the human aortic endothelial cells, through the downregulation of secretion of vascular endothelial growth factor from MDA-MB-231 cells.Taken together, our study suggests potential therapeutic effect of PL against invasive breast cancer.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research Laboratory, Methodist Research Institute, 1800 N Capitol Ave, E504, Indianapolis, IN 46202, USA. dsliva@clarian.org

ABSTRACT
The antitumour activity of a medicinal mushroom Phellinus linteus (PL), through the stimulation of immune system or the induction of apoptosis, has been recently described. However, the molecular mechanisms responsible for the inhibition of invasive behaviour of cancer cells remain to be addressed. In the present study, we demonstrate that PL inhibits proliferation (anchorage-dependent growth) as well as colony formation (anchorage-independent growth) of highly invasive human breast cancer cells. The growth inhibition of MDA-MB-231 cells is mediated by the cell cycle arrest at S phase through the upregulation of p27(Kip1) expression. Phellinus linteus also suppressed invasive behaviour of MDA-MB-231 cells by the inhibition of cell adhesion, cell migration and cell invasion through the suppression of secretion of urokinase-plasminogen activator from breast cancer cells. In addition, PL markedly inhibited the early event in angiogenesis, capillary morphogenesis of the human aortic endothelial cells, through the downregulation of secretion of vascular endothelial growth factor from MDA-MB-231 cells. These effects are mediated by the inhibition of serine-threonine kinase AKT signalling, because PL suppressed phosphorylation of AKT at Thr(308) and Ser(473) in breast cancer cells. Taken together, our study suggests potential therapeutic effect of PL against invasive breast cancer.

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Effect of PL on AKT activity. MDA-MB-231 cells were treated with PL (0–1.0 mg ml−1) for 24 h and whole-cell extracts were subjected to western blot analysis with (A) anti-p-AKT-Thr308 or (B) anti-p-AKT-Ser473 antibodies. The equal protein loading was verified with anti-AKT antibody. The level of pAKT (ratio pAKT/AKT) was quantified by densitometry as described in Materials and Methods. The results are representative of three separate experiments.
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fig6: Effect of PL on AKT activity. MDA-MB-231 cells were treated with PL (0–1.0 mg ml−1) for 24 h and whole-cell extracts were subjected to western blot analysis with (A) anti-p-AKT-Thr308 or (B) anti-p-AKT-Ser473 antibodies. The equal protein loading was verified with anti-AKT antibody. The level of pAKT (ratio pAKT/AKT) was quantified by densitometry as described in Materials and Methods. The results are representative of three separate experiments.

Mentions: AKT serine-threonine kinase (protein kinase B) regulates a variety of cellular processes through the phosphorylation of a wide spectrum of downstream substrates finally resulting in the expression of proteins involved in cell proliferation, invasiveness and angiogenesis among others (Woodgett, 2005; Dillon et al, 2007). To determine if PL modulates AKT activity in breast cancer cells, MDA-MB-231 cells were treated with PL (0–1.0 mg ml−1) for 24 h and the phosphorylation status of AKT evaluated in whole-cell extracts by western blot analysis. As seen in Figure 6A, PL inhibits phosphorylation of AKT at Thr308 in a dose–response manner. In addition, PL treatment also markedly decreased phosphorylation of AKT at Ser473 (Figure 6B).


Phellinus linteus suppresses growth, angiogenesis and invasive behaviour of breast cancer cells through the inhibition of AKT signalling.

Sliva D, Jedinak A, Kawasaki J, Harvey K, Slivova V - Br. J. Cancer (2008)

Effect of PL on AKT activity. MDA-MB-231 cells were treated with PL (0–1.0 mg ml−1) for 24 h and whole-cell extracts were subjected to western blot analysis with (A) anti-p-AKT-Thr308 or (B) anti-p-AKT-Ser473 antibodies. The equal protein loading was verified with anti-AKT antibody. The level of pAKT (ratio pAKT/AKT) was quantified by densitometry as described in Materials and Methods. The results are representative of three separate experiments.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2361714&req=5

fig6: Effect of PL on AKT activity. MDA-MB-231 cells were treated with PL (0–1.0 mg ml−1) for 24 h and whole-cell extracts were subjected to western blot analysis with (A) anti-p-AKT-Thr308 or (B) anti-p-AKT-Ser473 antibodies. The equal protein loading was verified with anti-AKT antibody. The level of pAKT (ratio pAKT/AKT) was quantified by densitometry as described in Materials and Methods. The results are representative of three separate experiments.
Mentions: AKT serine-threonine kinase (protein kinase B) regulates a variety of cellular processes through the phosphorylation of a wide spectrum of downstream substrates finally resulting in the expression of proteins involved in cell proliferation, invasiveness and angiogenesis among others (Woodgett, 2005; Dillon et al, 2007). To determine if PL modulates AKT activity in breast cancer cells, MDA-MB-231 cells were treated with PL (0–1.0 mg ml−1) for 24 h and the phosphorylation status of AKT evaluated in whole-cell extracts by western blot analysis. As seen in Figure 6A, PL inhibits phosphorylation of AKT at Thr308 in a dose–response manner. In addition, PL treatment also markedly decreased phosphorylation of AKT at Ser473 (Figure 6B).

Bottom Line: The growth inhibition of MDA-MB-231 cells is mediated by the cell cycle arrest at S phase through the upregulation of p27(Kip1) expression.In addition, PL markedly inhibited the early event in angiogenesis, capillary morphogenesis of the human aortic endothelial cells, through the downregulation of secretion of vascular endothelial growth factor from MDA-MB-231 cells.Taken together, our study suggests potential therapeutic effect of PL against invasive breast cancer.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research Laboratory, Methodist Research Institute, 1800 N Capitol Ave, E504, Indianapolis, IN 46202, USA. dsliva@clarian.org

ABSTRACT
The antitumour activity of a medicinal mushroom Phellinus linteus (PL), through the stimulation of immune system or the induction of apoptosis, has been recently described. However, the molecular mechanisms responsible for the inhibition of invasive behaviour of cancer cells remain to be addressed. In the present study, we demonstrate that PL inhibits proliferation (anchorage-dependent growth) as well as colony formation (anchorage-independent growth) of highly invasive human breast cancer cells. The growth inhibition of MDA-MB-231 cells is mediated by the cell cycle arrest at S phase through the upregulation of p27(Kip1) expression. Phellinus linteus also suppressed invasive behaviour of MDA-MB-231 cells by the inhibition of cell adhesion, cell migration and cell invasion through the suppression of secretion of urokinase-plasminogen activator from breast cancer cells. In addition, PL markedly inhibited the early event in angiogenesis, capillary morphogenesis of the human aortic endothelial cells, through the downregulation of secretion of vascular endothelial growth factor from MDA-MB-231 cells. These effects are mediated by the inhibition of serine-threonine kinase AKT signalling, because PL suppressed phosphorylation of AKT at Thr(308) and Ser(473) in breast cancer cells. Taken together, our study suggests potential therapeutic effect of PL against invasive breast cancer.

Show MeSH
Related in: MedlinePlus