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RasGAP-derived peptide GAP159 enhances cisplatin-induced cytotoxicity and apoptosis in HCT116 cells.

Zhang H, Zhang S, He H, Zhang C, Chen Y, Yu D, Chen J, Shao R - Acta Pharm Sin B (2014)

Bottom Line: This synergistic effect was associated with the inhibitions of phospho-AKT, phospho-ERK and NF-κB.In mouse colon tumor CT26 animal models, GAP159 combined with CDDP significantly suppressed CT26 tumor growth, and GAP159 alone showed slight inhibitory effect.Our data suggests that co-treatment of GAP159 and chemotherapeutics will become a potential therapeutic strategy for colon cancers.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.

ABSTRACT
To increase the efficacy of currently used anti-cancer genotoxins, one of the current efforts is to find agents that can sensitize cancer cells to genotoxins so that the efficacious doses of genotoxins can be lowered to reduce deleterious side-effects. In this study, we reported that a synthetic RasGAP-derived peptide GAP159 could enhance the effect of chemotherapeutic agent cisplatin (CDDP) in human colon carcinoma HCT116 cells. Our results showed that GAP159 significantly increased the CDDP-induced cytotoxicity and apoptosis in HCT116 cells. This synergistic effect was associated with the inhibitions of phospho-AKT, phospho-ERK and NF-κB. In mouse colon tumor CT26 animal models, GAP159 combined with CDDP significantly suppressed CT26 tumor growth, and GAP159 alone showed slight inhibitory effect. Our data suggests that co-treatment of GAP159 and chemotherapeutics will become a potential therapeutic strategy for colon cancers.

No MeSH data available.


Related in: MedlinePlus

Effects of GAP159 on Akt, ERK and NF-κB. A: Cells were treated with GAP159 in the absence or presence of CDDP for 48 h; B: quantification of protein levels. The protein levels were detected by Western blot.
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f0020: Effects of GAP159 on Akt, ERK and NF-κB. A: Cells were treated with GAP159 in the absence or presence of CDDP for 48 h; B: quantification of protein levels. The protein levels were detected by Western blot.

Mentions: Previously, we found that down-regulation of G3BP by peptides and siRNAs could impair Ras activity and inhibit downstream signaling pathways11,12. Therefore, GAP159 may affect the Ras pathways including ERK and NF-κB. In addition, extraordinary activation of ERK cascades by CDDP antagonizes apoptosis24. So, we detected the effect of GAP159 on CDDP induced activations of ERK and NF-κB. Western blot results showed that GAP159 clearly inhibited CDDP induced ERK activity and had no significant effect on total ERK protein levels (Fig. 4). We also determined if the GAP159 modulated Akt activity and sensitized HCT116 cells to CDDP. Fig. 4 shows that GAP159 inhibits Akt phosphorylation, and has no effect on total Akt expression. It has been reported that NF-κB activity could be modulated by ERK and Akt25. We also found that GAP159 significantly down-regulated NF-κB (Fig. 4).


RasGAP-derived peptide GAP159 enhances cisplatin-induced cytotoxicity and apoptosis in HCT116 cells.

Zhang H, Zhang S, He H, Zhang C, Chen Y, Yu D, Chen J, Shao R - Acta Pharm Sin B (2014)

Effects of GAP159 on Akt, ERK and NF-κB. A: Cells were treated with GAP159 in the absence or presence of CDDP for 48 h; B: quantification of protein levels. The protein levels were detected by Western blot.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4590723&req=5

f0020: Effects of GAP159 on Akt, ERK and NF-κB. A: Cells were treated with GAP159 in the absence or presence of CDDP for 48 h; B: quantification of protein levels. The protein levels were detected by Western blot.
Mentions: Previously, we found that down-regulation of G3BP by peptides and siRNAs could impair Ras activity and inhibit downstream signaling pathways11,12. Therefore, GAP159 may affect the Ras pathways including ERK and NF-κB. In addition, extraordinary activation of ERK cascades by CDDP antagonizes apoptosis24. So, we detected the effect of GAP159 on CDDP induced activations of ERK and NF-κB. Western blot results showed that GAP159 clearly inhibited CDDP induced ERK activity and had no significant effect on total ERK protein levels (Fig. 4). We also determined if the GAP159 modulated Akt activity and sensitized HCT116 cells to CDDP. Fig. 4 shows that GAP159 inhibits Akt phosphorylation, and has no effect on total Akt expression. It has been reported that NF-κB activity could be modulated by ERK and Akt25. We also found that GAP159 significantly down-regulated NF-κB (Fig. 4).

Bottom Line: This synergistic effect was associated with the inhibitions of phospho-AKT, phospho-ERK and NF-κB.In mouse colon tumor CT26 animal models, GAP159 combined with CDDP significantly suppressed CT26 tumor growth, and GAP159 alone showed slight inhibitory effect.Our data suggests that co-treatment of GAP159 and chemotherapeutics will become a potential therapeutic strategy for colon cancers.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.

ABSTRACT
To increase the efficacy of currently used anti-cancer genotoxins, one of the current efforts is to find agents that can sensitize cancer cells to genotoxins so that the efficacious doses of genotoxins can be lowered to reduce deleterious side-effects. In this study, we reported that a synthetic RasGAP-derived peptide GAP159 could enhance the effect of chemotherapeutic agent cisplatin (CDDP) in human colon carcinoma HCT116 cells. Our results showed that GAP159 significantly increased the CDDP-induced cytotoxicity and apoptosis in HCT116 cells. This synergistic effect was associated with the inhibitions of phospho-AKT, phospho-ERK and NF-κB. In mouse colon tumor CT26 animal models, GAP159 combined with CDDP significantly suppressed CT26 tumor growth, and GAP159 alone showed slight inhibitory effect. Our data suggests that co-treatment of GAP159 and chemotherapeutics will become a potential therapeutic strategy for colon cancers.

No MeSH data available.


Related in: MedlinePlus