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Lichen secondary metabolites in Flavocetraria cucullata exhibit anti-cancer effects on human cancer cells through the induction of apoptosis and suppression of tumorigenic potentials.

Nguyen TT, Yoon S, Yang Y, Lee HB, Oh S, Jeong MH, Kim JJ, Yee ST, Crişan F, Moon C, Lee KY, Kim KK, Hur JS, Kim H - PLoS ONE (2014)

Bottom Line: At a lethal dose, treatment with the extract or with usnic acid greatly increased the apoptotic cell population and specifically activated the apoptotic signaling pathway; however, using sub-lethal doses, extract and usnic acid treatment decreased cancer cell motility and inhibited in vitro and in vivo tumorigenic potentials.In these cells, we observed significantly reduced levels of epithelial-mesenchymal transition (EMT) markers and phosphor-Akt, while phosphor-c-Jun and phosphor-ERK1/2 levels were only marginally affected.Taken together, F. cucullata and its subcomponent, usnic acid together with additional component, exert anti-cancer effects on human cancer cells through the induction of apoptosis and the inhibition of EMT.

View Article: PubMed Central - PubMed

Affiliation: Korean Lichen Research Institute, Sunchon National University, Sunchon, Republic of Korea; Faculty of Natural Science and Technology, Tay Nguyen University, Buon Ma Thuot, Vietnam.

ABSTRACT
Lichens are symbiotic organisms which produce distinct secondary metabolic products. In the present study, we tested the cytotoxic activity of 17 lichen species against several human cancer cells and further investigated the molecular mechanisms underlying their anti-cancer activity. We found that among 17 lichens species, F. cucullata exhibited the most potent cytotoxicity in several human cancer cells. High performance liquid chromatography analysis revealed that the acetone extract of F. cucullata contains usnic acid, salazinic acid, Squamatic acid, Baeomycesic acid, d-protolichesterinic acid, and lichesterinic acid as subcomponents. MTT assay showed that cancer cell lines were more vulnerable to the cytotoxic effects of the extract than non-cancer cell lines. Furthermore, among the identified subcomponents, usnic acid treatment had a similar cytotoxic effect on cancer cell lines but with lower potency than the extract. At a lethal dose, treatment with the extract or with usnic acid greatly increased the apoptotic cell population and specifically activated the apoptotic signaling pathway; however, using sub-lethal doses, extract and usnic acid treatment decreased cancer cell motility and inhibited in vitro and in vivo tumorigenic potentials. In these cells, we observed significantly reduced levels of epithelial-mesenchymal transition (EMT) markers and phosphor-Akt, while phosphor-c-Jun and phosphor-ERK1/2 levels were only marginally affected. Overall, the anti-cancer activity of the extract is more potent than that of usnic acid alone. Taken together, F. cucullata and its subcomponent, usnic acid together with additional component, exert anti-cancer effects on human cancer cells through the induction of apoptosis and the inhibition of EMT.

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Suppression of epithelial-mesenchymal transition (EMT) by the acetone extract of F. cucullata and usnic acid in sub-lethal concentrations.(A) E-cadherin level in A549 cells treated with the F. cucullata extract, usnic acid, or lichesterinic acid for 48 hr, and quantificational analysis of E-cadherin band in each group. Values were obtained by measuring the intensity of E-cadherin band normalized to α-tubulin. (B) Quantitative analysis of the mRNA level of EMT markers in A549 cells treated with the F. cucullata extract, usnic acid, or lichesterinic acid for 48 hr. Data represent mean ± S.E.M. (standard error of the mean), n = 3. *p<0.05; **p<0.01; NS, no significant difference when compared to the dimethylsulfoxide-treated group; @p<0.05 when compared to the indicated group.
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pone-0111575-g007: Suppression of epithelial-mesenchymal transition (EMT) by the acetone extract of F. cucullata and usnic acid in sub-lethal concentrations.(A) E-cadherin level in A549 cells treated with the F. cucullata extract, usnic acid, or lichesterinic acid for 48 hr, and quantificational analysis of E-cadherin band in each group. Values were obtained by measuring the intensity of E-cadherin band normalized to α-tubulin. (B) Quantitative analysis of the mRNA level of EMT markers in A549 cells treated with the F. cucullata extract, usnic acid, or lichesterinic acid for 48 hr. Data represent mean ± S.E.M. (standard error of the mean), n = 3. *p<0.05; **p<0.01; NS, no significant difference when compared to the dimethylsulfoxide-treated group; @p<0.05 when compared to the indicated group.

Mentions: As F. cucullata and usnic acid were found to significantly decrease cancer cell motility and tumorigenicity, we then investigated whether epithelial-mesenchymal transition (EMT) plays a role in mediating these effects. The expression level of E-cadherin was analyzed in A549 cells treated with a sub-lethal concentration of F. cucullata, usnic acid, or lichesterinic acid. The data showed that the acetone extract of F. cucullata and usnic acid significantly increased the protein level of E-cadherin (Fig. 7A). Consistently, the expression level of E-cadherin mRNA was also increased in these cells, while mRNA levels of N-cadherin, Twist, and Snail were decreased in these cells. These findings indicate that F. cucullata and usnic acid can inhibit EMT (Fig. 7B). Lichesterinic acid treatment induced no significant changes in the levels of these EMT markers. In addition, changes in the phosphorylation levels of c-jun, Akt, and ERK1/2 were analyzed in A549 cells treated with a sub-lethal concentration of F. cucullata, usnic acid, or lichesterinic acid. As shown in Figure 8, the level of p-(Ser473)-Akt was dramatically decreased by both F. cucullata and usnic acid treatment in a dose-dependent manner while the levels of p-(Ser63)-c-jun and p-(Thr202/Tyr204, Thr185/Tyr187)-ERK1/2 were only marginally affected by usnic acid. These results suggest that sub-lethal concentrations F. cucullata extract and usnic acid can exert anti-cancer effects possibly through inhibiting EMT and Akt signaling.


Lichen secondary metabolites in Flavocetraria cucullata exhibit anti-cancer effects on human cancer cells through the induction of apoptosis and suppression of tumorigenic potentials.

Nguyen TT, Yoon S, Yang Y, Lee HB, Oh S, Jeong MH, Kim JJ, Yee ST, Crişan F, Moon C, Lee KY, Kim KK, Hur JS, Kim H - PLoS ONE (2014)

Suppression of epithelial-mesenchymal transition (EMT) by the acetone extract of F. cucullata and usnic acid in sub-lethal concentrations.(A) E-cadherin level in A549 cells treated with the F. cucullata extract, usnic acid, or lichesterinic acid for 48 hr, and quantificational analysis of E-cadherin band in each group. Values were obtained by measuring the intensity of E-cadherin band normalized to α-tubulin. (B) Quantitative analysis of the mRNA level of EMT markers in A549 cells treated with the F. cucullata extract, usnic acid, or lichesterinic acid for 48 hr. Data represent mean ± S.E.M. (standard error of the mean), n = 3. *p<0.05; **p<0.01; NS, no significant difference when compared to the dimethylsulfoxide-treated group; @p<0.05 when compared to the indicated group.
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pone-0111575-g007: Suppression of epithelial-mesenchymal transition (EMT) by the acetone extract of F. cucullata and usnic acid in sub-lethal concentrations.(A) E-cadherin level in A549 cells treated with the F. cucullata extract, usnic acid, or lichesterinic acid for 48 hr, and quantificational analysis of E-cadherin band in each group. Values were obtained by measuring the intensity of E-cadherin band normalized to α-tubulin. (B) Quantitative analysis of the mRNA level of EMT markers in A549 cells treated with the F. cucullata extract, usnic acid, or lichesterinic acid for 48 hr. Data represent mean ± S.E.M. (standard error of the mean), n = 3. *p<0.05; **p<0.01; NS, no significant difference when compared to the dimethylsulfoxide-treated group; @p<0.05 when compared to the indicated group.
Mentions: As F. cucullata and usnic acid were found to significantly decrease cancer cell motility and tumorigenicity, we then investigated whether epithelial-mesenchymal transition (EMT) plays a role in mediating these effects. The expression level of E-cadherin was analyzed in A549 cells treated with a sub-lethal concentration of F. cucullata, usnic acid, or lichesterinic acid. The data showed that the acetone extract of F. cucullata and usnic acid significantly increased the protein level of E-cadherin (Fig. 7A). Consistently, the expression level of E-cadherin mRNA was also increased in these cells, while mRNA levels of N-cadherin, Twist, and Snail were decreased in these cells. These findings indicate that F. cucullata and usnic acid can inhibit EMT (Fig. 7B). Lichesterinic acid treatment induced no significant changes in the levels of these EMT markers. In addition, changes in the phosphorylation levels of c-jun, Akt, and ERK1/2 were analyzed in A549 cells treated with a sub-lethal concentration of F. cucullata, usnic acid, or lichesterinic acid. As shown in Figure 8, the level of p-(Ser473)-Akt was dramatically decreased by both F. cucullata and usnic acid treatment in a dose-dependent manner while the levels of p-(Ser63)-c-jun and p-(Thr202/Tyr204, Thr185/Tyr187)-ERK1/2 were only marginally affected by usnic acid. These results suggest that sub-lethal concentrations F. cucullata extract and usnic acid can exert anti-cancer effects possibly through inhibiting EMT and Akt signaling.

Bottom Line: At a lethal dose, treatment with the extract or with usnic acid greatly increased the apoptotic cell population and specifically activated the apoptotic signaling pathway; however, using sub-lethal doses, extract and usnic acid treatment decreased cancer cell motility and inhibited in vitro and in vivo tumorigenic potentials.In these cells, we observed significantly reduced levels of epithelial-mesenchymal transition (EMT) markers and phosphor-Akt, while phosphor-c-Jun and phosphor-ERK1/2 levels were only marginally affected.Taken together, F. cucullata and its subcomponent, usnic acid together with additional component, exert anti-cancer effects on human cancer cells through the induction of apoptosis and the inhibition of EMT.

View Article: PubMed Central - PubMed

Affiliation: Korean Lichen Research Institute, Sunchon National University, Sunchon, Republic of Korea; Faculty of Natural Science and Technology, Tay Nguyen University, Buon Ma Thuot, Vietnam.

ABSTRACT
Lichens are symbiotic organisms which produce distinct secondary metabolic products. In the present study, we tested the cytotoxic activity of 17 lichen species against several human cancer cells and further investigated the molecular mechanisms underlying their anti-cancer activity. We found that among 17 lichens species, F. cucullata exhibited the most potent cytotoxicity in several human cancer cells. High performance liquid chromatography analysis revealed that the acetone extract of F. cucullata contains usnic acid, salazinic acid, Squamatic acid, Baeomycesic acid, d-protolichesterinic acid, and lichesterinic acid as subcomponents. MTT assay showed that cancer cell lines were more vulnerable to the cytotoxic effects of the extract than non-cancer cell lines. Furthermore, among the identified subcomponents, usnic acid treatment had a similar cytotoxic effect on cancer cell lines but with lower potency than the extract. At a lethal dose, treatment with the extract or with usnic acid greatly increased the apoptotic cell population and specifically activated the apoptotic signaling pathway; however, using sub-lethal doses, extract and usnic acid treatment decreased cancer cell motility and inhibited in vitro and in vivo tumorigenic potentials. In these cells, we observed significantly reduced levels of epithelial-mesenchymal transition (EMT) markers and phosphor-Akt, while phosphor-c-Jun and phosphor-ERK1/2 levels were only marginally affected. Overall, the anti-cancer activity of the extract is more potent than that of usnic acid alone. Taken together, F. cucullata and its subcomponent, usnic acid together with additional component, exert anti-cancer effects on human cancer cells through the induction of apoptosis and the inhibition of EMT.

Show MeSH
Related in: MedlinePlus