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Carnosine Inhibits the Proliferation of Human Gastric Carcinoma Cells by Retarding Akt/mTOR/p70S6K Signaling.

Zhang Z, Miao L, Wu X, Liu G, Peng Y, Xin X, Jiao B, Kong X - J Cancer (2014)

Bottom Line: Carnosine (β-alanyl-L-histidine), described as an enigmatic peptide for its antioxidant, anti-aging and especially antiproliferation properties, has been demonstrated to play an anti-tumorigenic role in certain types of cancer.The mTOR signaling axis molecules were analyzed in carnosine treated cells.The results showed that treatment with carnosine led to proliferation inhibition, cell cycle arrest in the G0/G1 phase, apoptosis increase, and inhibition of mTOR signaling activation by decreasing the phosphorylation of Akt, mTOR and p70S6K, suggesting that proliferation inhibition of carnosine in human gastric carcinoma was through the inhibition of Akt/mTOR/p70S6K pathway, and carnosine would be a mimic of rapamycin.

View Article: PubMed Central - PubMed

Affiliation: 1. Key Laboratory of Liver Disease, Center of Infectious Diseases, Guangzhou 458 Hospital, Guangzhou, China ; 3. Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai, China.

ABSTRACT
Carnosine (β-alanyl-L-histidine), described as an enigmatic peptide for its antioxidant, anti-aging and especially antiproliferation properties, has been demonstrated to play an anti-tumorigenic role in certain types of cancer. However, its function in human gastric carcinoma remains unclear. In this study, the effect of carnosine on cell proliferation and its underlying mechanisms were investigated in the cultured human gastric carcinoma cells. The mTOR signaling axis molecules were analyzed in carnosine treated cells. The results showed that treatment with carnosine led to proliferation inhibition, cell cycle arrest in the G0/G1 phase, apoptosis increase, and inhibition of mTOR signaling activation by decreasing the phosphorylation of Akt, mTOR and p70S6K, suggesting that proliferation inhibition of carnosine in human gastric carcinoma was through the inhibition of Akt/mTOR/p70S6K pathway, and carnosine would be a mimic of rapamycin.

No MeSH data available.


Related in: MedlinePlus

Carnosine induces apoptosis in human gastric carcinoma cells. (A) Following treatment of SGC-7901 and MKN45 cells with carnosine (50 and 100 mM) and rapamycin (20 nM) for 24 h, apoptotic cells of the two cell lines were detected by Annexin V and propidium iodide double staining. Statistical analysis of the percentages of the apoptotic cells. (B) Western blots of whole-cell extracts of treated cells were analyzed for Bcl-2, Bad and cleaved-PARP after treatment with carnosine and rapamycin for 48 h. The data shown are representatives of three experiments. *P<0.05, **P<0.01.
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Figure 3: Carnosine induces apoptosis in human gastric carcinoma cells. (A) Following treatment of SGC-7901 and MKN45 cells with carnosine (50 and 100 mM) and rapamycin (20 nM) for 24 h, apoptotic cells of the two cell lines were detected by Annexin V and propidium iodide double staining. Statistical analysis of the percentages of the apoptotic cells. (B) Western blots of whole-cell extracts of treated cells were analyzed for Bcl-2, Bad and cleaved-PARP after treatment with carnosine and rapamycin for 48 h. The data shown are representatives of three experiments. *P<0.05, **P<0.01.

Mentions: Next, we examined whether and how carnosine induces apoptosis in gastric carcinoma cells. Two cell lines were treated with carnosine (50 and 100 mM) and rapamycin (20 nM) for 24 h, and the apoptotic cells were detected by Annexin V and propidium iodide double staining. As observed in Fig. 3A, treatment with carnosine resulted in a marked dose-dependent increase in apoptosis in both cell lines. Carnosine (at 50 mM concentration) showed a similar effect with rapamycin (20 nM) in SGC-7901 cells, but better than rapamycin in MKN45 cells. To understand the possible mechanism responsible for carnosine-induced apoptotic activity, pivotal proteins associated with apoptosis in the treated cells were examined. The Bcl-2 family, which consists of anti-apoptotic group (Bcl-2, Bcl-xl) and apoptotic group (Bax, Bad), plays a crucial role in regulation of apoptosis through the mitochondrial pathway22. The cleaved PARP (a substrate of caspase-3) is reported to prevent depletion of NAD and ATP that are required for the apoptotic program23. Western blot analysis in two cell lines showed that treatment with carnosine induced a decreased level of anti-apoptotic Bcl-2, but an increased level of apoptotic Bad. Meanwhile, increased cleaved PARP was also observed. Consistently, rapamycin exerted a similar effect on the expression of those proteins (Fig. 3B). These results reveal that carnosine-induced cell apoptosis is partially mediated by the mitochondria pathway and caspase activation.


Carnosine Inhibits the Proliferation of Human Gastric Carcinoma Cells by Retarding Akt/mTOR/p70S6K Signaling.

Zhang Z, Miao L, Wu X, Liu G, Peng Y, Xin X, Jiao B, Kong X - J Cancer (2014)

Carnosine induces apoptosis in human gastric carcinoma cells. (A) Following treatment of SGC-7901 and MKN45 cells with carnosine (50 and 100 mM) and rapamycin (20 nM) for 24 h, apoptotic cells of the two cell lines were detected by Annexin V and propidium iodide double staining. Statistical analysis of the percentages of the apoptotic cells. (B) Western blots of whole-cell extracts of treated cells were analyzed for Bcl-2, Bad and cleaved-PARP after treatment with carnosine and rapamycin for 48 h. The data shown are representatives of three experiments. *P<0.05, **P<0.01.
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Figure 3: Carnosine induces apoptosis in human gastric carcinoma cells. (A) Following treatment of SGC-7901 and MKN45 cells with carnosine (50 and 100 mM) and rapamycin (20 nM) for 24 h, apoptotic cells of the two cell lines were detected by Annexin V and propidium iodide double staining. Statistical analysis of the percentages of the apoptotic cells. (B) Western blots of whole-cell extracts of treated cells were analyzed for Bcl-2, Bad and cleaved-PARP after treatment with carnosine and rapamycin for 48 h. The data shown are representatives of three experiments. *P<0.05, **P<0.01.
Mentions: Next, we examined whether and how carnosine induces apoptosis in gastric carcinoma cells. Two cell lines were treated with carnosine (50 and 100 mM) and rapamycin (20 nM) for 24 h, and the apoptotic cells were detected by Annexin V and propidium iodide double staining. As observed in Fig. 3A, treatment with carnosine resulted in a marked dose-dependent increase in apoptosis in both cell lines. Carnosine (at 50 mM concentration) showed a similar effect with rapamycin (20 nM) in SGC-7901 cells, but better than rapamycin in MKN45 cells. To understand the possible mechanism responsible for carnosine-induced apoptotic activity, pivotal proteins associated with apoptosis in the treated cells were examined. The Bcl-2 family, which consists of anti-apoptotic group (Bcl-2, Bcl-xl) and apoptotic group (Bax, Bad), plays a crucial role in regulation of apoptosis through the mitochondrial pathway22. The cleaved PARP (a substrate of caspase-3) is reported to prevent depletion of NAD and ATP that are required for the apoptotic program23. Western blot analysis in two cell lines showed that treatment with carnosine induced a decreased level of anti-apoptotic Bcl-2, but an increased level of apoptotic Bad. Meanwhile, increased cleaved PARP was also observed. Consistently, rapamycin exerted a similar effect on the expression of those proteins (Fig. 3B). These results reveal that carnosine-induced cell apoptosis is partially mediated by the mitochondria pathway and caspase activation.

Bottom Line: Carnosine (β-alanyl-L-histidine), described as an enigmatic peptide for its antioxidant, anti-aging and especially antiproliferation properties, has been demonstrated to play an anti-tumorigenic role in certain types of cancer.The mTOR signaling axis molecules were analyzed in carnosine treated cells.The results showed that treatment with carnosine led to proliferation inhibition, cell cycle arrest in the G0/G1 phase, apoptosis increase, and inhibition of mTOR signaling activation by decreasing the phosphorylation of Akt, mTOR and p70S6K, suggesting that proliferation inhibition of carnosine in human gastric carcinoma was through the inhibition of Akt/mTOR/p70S6K pathway, and carnosine would be a mimic of rapamycin.

View Article: PubMed Central - PubMed

Affiliation: 1. Key Laboratory of Liver Disease, Center of Infectious Diseases, Guangzhou 458 Hospital, Guangzhou, China ; 3. Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai, China.

ABSTRACT
Carnosine (β-alanyl-L-histidine), described as an enigmatic peptide for its antioxidant, anti-aging and especially antiproliferation properties, has been demonstrated to play an anti-tumorigenic role in certain types of cancer. However, its function in human gastric carcinoma remains unclear. In this study, the effect of carnosine on cell proliferation and its underlying mechanisms were investigated in the cultured human gastric carcinoma cells. The mTOR signaling axis molecules were analyzed in carnosine treated cells. The results showed that treatment with carnosine led to proliferation inhibition, cell cycle arrest in the G0/G1 phase, apoptosis increase, and inhibition of mTOR signaling activation by decreasing the phosphorylation of Akt, mTOR and p70S6K, suggesting that proliferation inhibition of carnosine in human gastric carcinoma was through the inhibition of Akt/mTOR/p70S6K pathway, and carnosine would be a mimic of rapamycin.

No MeSH data available.


Related in: MedlinePlus