Limits...
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.

Show MeSH

Related in: MedlinePlus

The effect of ilimaquinone and ethylsmenoquinone on colon cancer cell growth. (A,B) HCT116 (A) and RKO (B) cells were incubated for 24 h with the indicated concentrations of IQ and ESQ. Cell viability was examined using the CellTiter-Glo assay (Promega); (C,D) HCT116 (C) and RKO (D) cells were incubated with the vehicle (DMSO) or IQ and ESQ for 24 h. After incubation, cells were harvested and stained with propidium iodide (PI) and analyzed using a cytometer. The x-axis indicates the PI fluorescence intensity that correlates with the DNA content.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4306951&req=5

marinedrugs-13-00543-f004: The effect of ilimaquinone and ethylsmenoquinone on colon cancer cell growth. (A,B) HCT116 (A) and RKO (B) cells were incubated for 24 h with the indicated concentrations of IQ and ESQ. Cell viability was examined using the CellTiter-Glo assay (Promega); (C,D) HCT116 (C) and RKO (D) cells were incubated with the vehicle (DMSO) or IQ and ESQ for 24 h. After incubation, cells were harvested and stained with propidium iodide (PI) and analyzed using a cytometer. The x-axis indicates the PI fluorescence intensity that correlates with the DNA content.

Mentions: Previous studies have reported that p53, which is stabilized by certain anti-cancer drugs (e.g., doxorubicin and camptothecin), suppresses the proliferation of various cancer cells [18]. In light of the fact that ilimaquinone and ethylsmenoquinone induce the accumulation of p53, we postulated that these sesquiterpene quinones may also inhibit the growth of colon cancer cells. As expected, ilimaquinone and ethylsmenoquinone efficiently reduced the proliferation of both HCT116 and RKO cancer cells in a concentration-dependent manner (Figure 4A,B). To investigate the possible mechanism for ilimaquinone and ethylsmenoquinone-induced growth inhibition, cell cycle distribution after cell exposure to these compounds was analyzed using propidium iodide (PI) staining. When HCT116 were incubated with ilimaquinone and ethylsmenoquinone, the populations of cells in the G2/M phase increased from 28.4% to 53.8% and 27.1% to 52.7%, respectively. Similarly, when RKO cells were treated with ilimaquinone and ethylsmenoquinone, the G2/M phase cell populations increased from 33.6% to 49.7% and from 25.8% to 43%, respectively, compared with the vehicle control (Figure 4C,D). These results indicate that ilimaquinone and ethylsmenoquinone suppress the growth of colon cancer cells expressing wild-type p53 by inducing G2/M cell cycle arrest.


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)

The effect of ilimaquinone and ethylsmenoquinone on colon cancer cell growth. (A,B) HCT116 (A) and RKO (B) cells were incubated for 24 h with the indicated concentrations of IQ and ESQ. Cell viability was examined using the CellTiter-Glo assay (Promega); (C,D) HCT116 (C) and RKO (D) cells were incubated with the vehicle (DMSO) or IQ and ESQ for 24 h. After incubation, cells were harvested and stained with propidium iodide (PI) and analyzed using a cytometer. The x-axis indicates the PI fluorescence intensity that correlates with the DNA content.
© Copyright Policy
Related In: Results  -  Collection

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

marinedrugs-13-00543-f004: The effect of ilimaquinone and ethylsmenoquinone on colon cancer cell growth. (A,B) HCT116 (A) and RKO (B) cells were incubated for 24 h with the indicated concentrations of IQ and ESQ. Cell viability was examined using the CellTiter-Glo assay (Promega); (C,D) HCT116 (C) and RKO (D) cells were incubated with the vehicle (DMSO) or IQ and ESQ for 24 h. After incubation, cells were harvested and stained with propidium iodide (PI) and analyzed using a cytometer. The x-axis indicates the PI fluorescence intensity that correlates with the DNA content.
Mentions: Previous studies have reported that p53, which is stabilized by certain anti-cancer drugs (e.g., doxorubicin and camptothecin), suppresses the proliferation of various cancer cells [18]. In light of the fact that ilimaquinone and ethylsmenoquinone induce the accumulation of p53, we postulated that these sesquiterpene quinones may also inhibit the growth of colon cancer cells. As expected, ilimaquinone and ethylsmenoquinone efficiently reduced the proliferation of both HCT116 and RKO cancer cells in a concentration-dependent manner (Figure 4A,B). To investigate the possible mechanism for ilimaquinone and ethylsmenoquinone-induced growth inhibition, cell cycle distribution after cell exposure to these compounds was analyzed using propidium iodide (PI) staining. When HCT116 were incubated with ilimaquinone and ethylsmenoquinone, the populations of cells in the G2/M phase increased from 28.4% to 53.8% and 27.1% to 52.7%, respectively. Similarly, when RKO cells were treated with ilimaquinone and ethylsmenoquinone, the G2/M phase cell populations increased from 33.6% to 49.7% and from 25.8% to 43%, respectively, compared with the vehicle control (Figure 4C,D). These results indicate that ilimaquinone and ethylsmenoquinone suppress the growth of colon cancer cells expressing wild-type p53 by inducing G2/M cell cycle arrest.

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