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Activation of p53 with ilimaquinone and ethylsmenoquinone, marine sponge metabolites, induces apoptosis and autophagy in colon cancer cells.

Lee HY, Chung KJ, Hwang IH, Gwak J, Park S, Ju BG, Yun E, Kim DE, Chung YH, Na M, Song GY, Oh S - Mar Drugs (2015)

Bottom Line: Here, we used a cell-based reporter system for the detection of p53 response transcription to identify the marine sponge metabolites, ilimaquinone and ethylsmenoquinone, as activators of the p53 pathway.Furthermore, autophagy was elicited by both compounds, as indicated by microtubule-associated protein 1 light chain 3 (LC3) puncta formations and LC3-II turnover in HCT116 cells.Our findings suggest that ilimaquinone and ethylsmenoquinone exert their anti-cancer activity by activation of the p53 pathway and may have significant potential as chemo-preventive and therapeutic agents for human colon cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul 136-702, Korea. IHyunYoungg@gmail.com.

ABSTRACT
The tumor suppressor, p53, plays an essential role in the cellular response to stress through regulating the expression of genes involved in cell cycle arrest, apoptosis and autophagy. Here, we used a cell-based reporter system for the detection of p53 response transcription to identify the marine sponge metabolites, ilimaquinone and ethylsmenoquinone, as activators of the p53 pathway. We demonstrated that ilimaquinone and ethylsmenoquinone efficiently stabilize the p53 protein through promotion of p53 phosphorylation at Ser15 in both HCT116 and RKO colon cancer cells. Moreover, both compounds upregulate the expression of p21WAF1/CIP1, a p53-dependent gene, and suppress proliferation of colon cancer cells. In addition, ilimaquinone and ethylsmenoquinone induced G2/M cell cycle arrest and increased caspase-3 cleavage and the population of cells that positively stained with Annexin V-FITC, both of which are typical biochemical markers of apoptosis. Furthermore, autophagy was elicited by both compounds, as indicated by microtubule-associated protein 1 light chain 3 (LC3) puncta formations and LC3-II turnover in HCT116 cells. Our findings suggest that ilimaquinone and ethylsmenoquinone exert their anti-cancer activity by activation of the p53 pathway and may have significant potential as chemo-preventive and therapeutic agents for human colon cancer.

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(A) Chemical structure of ilimaquinone (IQ) and ethylsmenoquinone (ESQ); (B,C) concentration-dependent activation of p53 response transcription by IQ and ESQ. HCT116-p53 FL and RKO-p53 FL reporter cells were incubated with the indicated concentrations of IQ and ESQ. After 15 h, firefly luciferase activity was determined. The results represent the average of three experiments. Bars indicate standard deviations.
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marinedrugs-13-00543-f001: (A) Chemical structure of ilimaquinone (IQ) and ethylsmenoquinone (ESQ); (B,C) concentration-dependent activation of p53 response transcription by IQ and ESQ. HCT116-p53 FL and RKO-p53 FL reporter cells were incubated with the indicated concentrations of IQ and ESQ. After 15 h, firefly luciferase activity was determined. The results represent the average of three experiments. Bars indicate standard deviations.

Mentions: To identify natural product-derived activators of the p53 signaling pathway, we stably transfected a synthetic p53-dependent luciferase reporter plasmid into HCT116 colon cancer cells, which harbor the wild-type p53 gene [16], thus generating HCT116-p53 firefly luciferase (FL) reporter cells. Screening of natural compounds with the HCT116-p53 FL reporter cells revealed that ilimaquinone and ethylsmenoquinone robustly activate p53 responsive transcription (Supplementary Figure S1 and Figure 1A; Supplementary Table 1). Treatment of HCT116-FL reporter cells with increasing concentrations of ilimaquinone and ethylsmenoquinone caused a dose-dependent activation of p53 responsive transcription (Figure 1C). Consistent with this result, we found that p53-driven FL activity was similarly upregulated by both compounds in RKO colon cancer cells (Figure 1D), which also express wild-type p53 [17].


Activation of p53 with ilimaquinone and ethylsmenoquinone, marine sponge metabolites, induces apoptosis and autophagy in colon cancer cells.

Lee HY, Chung KJ, Hwang IH, Gwak J, Park S, Ju BG, Yun E, Kim DE, Chung YH, Na M, Song GY, Oh S - Mar Drugs (2015)

(A) Chemical structure of ilimaquinone (IQ) and ethylsmenoquinone (ESQ); (B,C) concentration-dependent activation of p53 response transcription by IQ and ESQ. HCT116-p53 FL and RKO-p53 FL reporter cells were incubated with the indicated concentrations of IQ and ESQ. After 15 h, firefly luciferase activity was determined. The results represent the average of three experiments. Bars indicate standard deviations.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4306951&req=5

marinedrugs-13-00543-f001: (A) Chemical structure of ilimaquinone (IQ) and ethylsmenoquinone (ESQ); (B,C) concentration-dependent activation of p53 response transcription by IQ and ESQ. HCT116-p53 FL and RKO-p53 FL reporter cells were incubated with the indicated concentrations of IQ and ESQ. After 15 h, firefly luciferase activity was determined. The results represent the average of three experiments. Bars indicate standard deviations.
Mentions: To identify natural product-derived activators of the p53 signaling pathway, we stably transfected a synthetic p53-dependent luciferase reporter plasmid into HCT116 colon cancer cells, which harbor the wild-type p53 gene [16], thus generating HCT116-p53 firefly luciferase (FL) reporter cells. Screening of natural compounds with the HCT116-p53 FL reporter cells revealed that ilimaquinone and ethylsmenoquinone robustly activate p53 responsive transcription (Supplementary Figure S1 and Figure 1A; Supplementary Table 1). Treatment of HCT116-FL reporter cells with increasing concentrations of ilimaquinone and ethylsmenoquinone caused a dose-dependent activation of p53 responsive transcription (Figure 1C). Consistent with this result, we found that p53-driven FL activity was similarly upregulated by both compounds in RKO colon cancer cells (Figure 1D), which also express wild-type p53 [17].

Bottom Line: Here, we used a cell-based reporter system for the detection of p53 response transcription to identify the marine sponge metabolites, ilimaquinone and ethylsmenoquinone, as activators of the p53 pathway.Furthermore, autophagy was elicited by both compounds, as indicated by microtubule-associated protein 1 light chain 3 (LC3) puncta formations and LC3-II turnover in HCT116 cells.Our findings suggest that ilimaquinone and ethylsmenoquinone exert their anti-cancer activity by activation of the p53 pathway and may have significant potential as chemo-preventive and therapeutic agents for human colon cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul 136-702, Korea. IHyunYoungg@gmail.com.

ABSTRACT
The tumor suppressor, p53, plays an essential role in the cellular response to stress through regulating the expression of genes involved in cell cycle arrest, apoptosis and autophagy. Here, we used a cell-based reporter system for the detection of p53 response transcription to identify the marine sponge metabolites, ilimaquinone and ethylsmenoquinone, as activators of the p53 pathway. We demonstrated that ilimaquinone and ethylsmenoquinone efficiently stabilize the p53 protein through promotion of p53 phosphorylation at Ser15 in both HCT116 and RKO colon cancer cells. Moreover, both compounds upregulate the expression of p21WAF1/CIP1, a p53-dependent gene, and suppress proliferation of colon cancer cells. In addition, ilimaquinone and ethylsmenoquinone induced G2/M cell cycle arrest and increased caspase-3 cleavage and the population of cells that positively stained with Annexin V-FITC, both of which are typical biochemical markers of apoptosis. Furthermore, autophagy was elicited by both compounds, as indicated by microtubule-associated protein 1 light chain 3 (LC3) puncta formations and LC3-II turnover in HCT116 cells. Our findings suggest that ilimaquinone and ethylsmenoquinone exert their anti-cancer activity by activation of the p53 pathway and may have significant potential as chemo-preventive and therapeutic agents for human colon cancer.

Show MeSH
Related in: MedlinePlus