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Pterostilbene exerts antitumor activity via the Notch1 signaling pathway in human lung adenocarcinoma cells.

Yang Y, Yan X, Duan W, Yan J, Yi W, Liang Z, Wang N, Li Y, Chen W, Yu S, Jin Z, Yi D - PLoS ONE (2013)

Bottom Line: PTE treatment resulted in a dose- and time-dependent decrease in the viability of A549 cells.DAPT (a gamma secretase inhibitor) and Notch1 siRNA prevented the induction of NICD and Hes1 activation by PTE treatment and sensitized the cells to PTE treatment.The down-regulation of Notch signaling also prevented the activation of pro-survival pathways (most notably the PI3K/Akt pathway) after PTE treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an City, China.

ABSTRACT
Although pterostilbene (PTE) has been shown to have potent antitumor activities against various cancer types, the molecular mechanisms of these activities remain unclear. In this study, we investigated the antitumor activity of PTE against human lung adenocarcinoma in vitro and in vivo and explored the role of the Notch1 signaling pathway in this process. PTE treatment resulted in a dose- and time-dependent decrease in the viability of A549 cells. Additionally, PTE exhibited strong antitumor activity, as evidenced not only by a reduced mitochondrial membrane potential (MMP) and a decreased intracellular glutathione content but also by increases in the apoptotic index and the level of reactive oxygen species (ROS). Furthermore, PTE treatment induced the activation of the Notch1 Intracellular Domain (NICD) protein and activated Hes1. DAPT (a gamma secretase inhibitor) and Notch1 siRNA prevented the induction of NICD and Hes1 activation by PTE treatment and sensitized the cells to PTE treatment. The down-regulation of Notch signaling also prevented the activation of pro-survival pathways (most notably the PI3K/Akt pathway) after PTE treatment. In summary, lung adenocarcinoma cells may enhance Notch1 activation as a protective mechanism in response to PTE treatment. Combining a gamma secretase inhibitor with PTE treatment may represent a novel approach for treating lung adenocarcinoma by inhibiting the survival pathways of cancer cells.

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The effects of PTE combined with DAPT on tumor xenografts in vivo.(A) Photographs showing the morphology of the tumor xenografts in different groups. (B) The tumor growth curve was drawn using the tumor volume and the treatment duration. (C) Representative Western blot results are shown. The results are expressed as the mean ± SEM, n = 3. **P<0.01 compared with the control group, ##P<0.01 compared with the PTE group, $$P<0.01 compared with the PTE+DAPT group. PTE, pterostilbene.
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pone-0062652-g009: The effects of PTE combined with DAPT on tumor xenografts in vivo.(A) Photographs showing the morphology of the tumor xenografts in different groups. (B) The tumor growth curve was drawn using the tumor volume and the treatment duration. (C) Representative Western blot results are shown. The results are expressed as the mean ± SEM, n = 3. **P<0.01 compared with the control group, ##P<0.01 compared with the PTE group, $$P<0.01 compared with the PTE+DAPT group. PTE, pterostilbene.

Mentions: To determine whether PTE can inhibit tumor growth in animals, we established A549 xenografts in athymic nude mice. We found that the mice in all treatment groups developed subcutaneous tumors. As shown in Figures 9A and 9B, treatment with PTE or DAPT alone significantly inhibited tumor growth (P<0.01, compared with the control group). The combination of DAPT and PTE further inhibited tumor growth (P<0.01, compared with the PTE group or the DAPT group). To further investigate whether PTE or/and DAPT regulates Notch1 signaling in vivo, we examined NICD and Hes1 expression in tumor tissues. Western blot analysis showed that the expression levels of NICD and Hes1 were significantly higher in tumors from the PTE-treated mice (P<0.01, compared with the control group, Figure 9C). As expected, co-treatment with PTE and DAPT inhibited NICD and Hes1 expression (P<0.01, compared with the PTE group, Figure 9C). In addition, co-treatment with PTE and DAPT decreased the phosphorylation of Akt at Serine 473 (P<0.01, compared with the PTE group). Next, we determined if the suppression of Akt with LY would alter the sensitization effect of PTE. LY not only effectively suppressed the level of phosphorylated Akt protein (Figure 10C) but also further enhanced the tumor growth inhibition induced by PTE treatment (Figures 10A and 10B).


Pterostilbene exerts antitumor activity via the Notch1 signaling pathway in human lung adenocarcinoma cells.

Yang Y, Yan X, Duan W, Yan J, Yi W, Liang Z, Wang N, Li Y, Chen W, Yu S, Jin Z, Yi D - PLoS ONE (2013)

The effects of PTE combined with DAPT on tumor xenografts in vivo.(A) Photographs showing the morphology of the tumor xenografts in different groups. (B) The tumor growth curve was drawn using the tumor volume and the treatment duration. (C) Representative Western blot results are shown. The results are expressed as the mean ± SEM, n = 3. **P<0.01 compared with the control group, ##P<0.01 compared with the PTE group, $$P<0.01 compared with the PTE+DAPT group. PTE, pterostilbene.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3643961&req=5

pone-0062652-g009: The effects of PTE combined with DAPT on tumor xenografts in vivo.(A) Photographs showing the morphology of the tumor xenografts in different groups. (B) The tumor growth curve was drawn using the tumor volume and the treatment duration. (C) Representative Western blot results are shown. The results are expressed as the mean ± SEM, n = 3. **P<0.01 compared with the control group, ##P<0.01 compared with the PTE group, $$P<0.01 compared with the PTE+DAPT group. PTE, pterostilbene.
Mentions: To determine whether PTE can inhibit tumor growth in animals, we established A549 xenografts in athymic nude mice. We found that the mice in all treatment groups developed subcutaneous tumors. As shown in Figures 9A and 9B, treatment with PTE or DAPT alone significantly inhibited tumor growth (P<0.01, compared with the control group). The combination of DAPT and PTE further inhibited tumor growth (P<0.01, compared with the PTE group or the DAPT group). To further investigate whether PTE or/and DAPT regulates Notch1 signaling in vivo, we examined NICD and Hes1 expression in tumor tissues. Western blot analysis showed that the expression levels of NICD and Hes1 were significantly higher in tumors from the PTE-treated mice (P<0.01, compared with the control group, Figure 9C). As expected, co-treatment with PTE and DAPT inhibited NICD and Hes1 expression (P<0.01, compared with the PTE group, Figure 9C). In addition, co-treatment with PTE and DAPT decreased the phosphorylation of Akt at Serine 473 (P<0.01, compared with the PTE group). Next, we determined if the suppression of Akt with LY would alter the sensitization effect of PTE. LY not only effectively suppressed the level of phosphorylated Akt protein (Figure 10C) but also further enhanced the tumor growth inhibition induced by PTE treatment (Figures 10A and 10B).

Bottom Line: PTE treatment resulted in a dose- and time-dependent decrease in the viability of A549 cells.DAPT (a gamma secretase inhibitor) and Notch1 siRNA prevented the induction of NICD and Hes1 activation by PTE treatment and sensitized the cells to PTE treatment.The down-regulation of Notch signaling also prevented the activation of pro-survival pathways (most notably the PI3K/Akt pathway) after PTE treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an City, China.

ABSTRACT
Although pterostilbene (PTE) has been shown to have potent antitumor activities against various cancer types, the molecular mechanisms of these activities remain unclear. In this study, we investigated the antitumor activity of PTE against human lung adenocarcinoma in vitro and in vivo and explored the role of the Notch1 signaling pathway in this process. PTE treatment resulted in a dose- and time-dependent decrease in the viability of A549 cells. Additionally, PTE exhibited strong antitumor activity, as evidenced not only by a reduced mitochondrial membrane potential (MMP) and a decreased intracellular glutathione content but also by increases in the apoptotic index and the level of reactive oxygen species (ROS). Furthermore, PTE treatment induced the activation of the Notch1 Intracellular Domain (NICD) protein and activated Hes1. DAPT (a gamma secretase inhibitor) and Notch1 siRNA prevented the induction of NICD and Hes1 activation by PTE treatment and sensitized the cells to PTE treatment. The down-regulation of Notch signaling also prevented the activation of pro-survival pathways (most notably the PI3K/Akt pathway) after PTE treatment. In summary, lung adenocarcinoma cells may enhance Notch1 activation as a protective mechanism in response to PTE treatment. Combining a gamma secretase inhibitor with PTE treatment may represent a novel approach for treating lung adenocarcinoma by inhibiting the survival pathways of cancer cells.

Show MeSH
Related in: MedlinePlus