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Metformin potentiates rapamycin and cisplatin in gastric cancer in mice.

Yu G, Fang W, Xia T, Chen Y, Gao Y, Jiao X, Huang S, Wang J, Li Z, Xie K - Oncotarget (2015)

Bottom Line: Also it enhanced cisplatin- or rapamycin-induced reduction of tumor growth as compared with treatment of either drug alone.In addition to activation of AMPK and suppression of the mTOR pathway, a series of increased and decreased genes expression were induced by metformin, including PTEN, MMP7, and FN1.We suggest that metformin could potentially be used for the treatment of gastric cancer especially in combination with cisplatin or rapamycin.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Changzheng Hospital, Shanghai 200070, China.

ABSTRACT
Here we showed that pAMPKα and PTEN were down-regulated and p-mTOR, p-S6, p-4EBP1, MMP7, and DCN1 were up-regulated in human gastric cancer tissue samples as compared to that in the noncancerous tissues. Metformin inhibited tumor growth in mice. Also it enhanced cisplatin- or rapamycin-induced reduction of tumor growth as compared with treatment of either drug alone. In addition to activation of AMPK and suppression of the mTOR pathway, a series of increased and decreased genes expression were induced by metformin, including PTEN, MMP7, and FN1. We suggest that metformin could potentially be used for the treatment of gastric cancer especially in combination with cisplatin or rapamycin.

No MeSH data available.


Related in: MedlinePlus

Metformin treatment led to aberrant expression of invasion/migration-related genes(A) Heatmap representing hierarchical clustering of all genes that displayed a 1.5-fold or greater difference in transcript levels in metformin-treated BGC823 cells with a concentration of 20 mM compared to controls at days 0, 24 h, and 48 h (B) Significant gene ontology (GO) terms retrieved by clusters D–G. (C) Pearson correlation network of the metformin action course generated using the Spring-embedded algorithm in Cytoscape. Partial genes in enriched GO categories are represented in the network. Nodes represent genes, and connections represent correlation coefficient.
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Figure 5: Metformin treatment led to aberrant expression of invasion/migration-related genes(A) Heatmap representing hierarchical clustering of all genes that displayed a 1.5-fold or greater difference in transcript levels in metformin-treated BGC823 cells with a concentration of 20 mM compared to controls at days 0, 24 h, and 48 h (B) Significant gene ontology (GO) terms retrieved by clusters D–G. (C) Pearson correlation network of the metformin action course generated using the Spring-embedded algorithm in Cytoscape. Partial genes in enriched GO categories are represented in the network. Nodes represent genes, and connections represent correlation coefficient.

Mentions: In a global gene expression analysis, we found that 2025 genes were differentially expressed (1092 up-regulated and 933 down-regulated) at 24 h, while 503 were differentially expressed (280 up-regulated and 223 down-regulated) at 48 h (Figure 5A). These genes were clustered by expression pattern, yield several distinct clusters (such as, cell cycle, regulation of cellular process, regulation of biological process, metabolic process, etc.) (Figure 5B). According to gene expression patterns changed in the enriched GO categories, we created a network diagram to illustrate how these genes work over time by computing a Pearson correlation coefficient of all differentially expressed genes (Figure 5C). Our further analysis revealed that PTEN, a key inhibitor of Akt/mTOR pathway [20, 21], and CDKN1, a potent cyclin-dependent kinase inhibitor [22], were up-regulated at early stage after treated by metformin. However, genes associated with matrix degradation and tumor invasion displayed lower expression when treated with metformin persistently. These genes included DCN, CLDN1, FN1, MMP7, WFDC1, and UBD [23]. Strikingly, we observed that mRNA levels of DCN, MMP7, and WFDC1 didn't changed compared to control at earlier stage (24 h), but sharply reduced at later stage (48 h). Together, these data provided new evidences that sustained treatment of metformin leads to continuous damage of the ability of cell proliferation and invasion/migration.


Metformin potentiates rapamycin and cisplatin in gastric cancer in mice.

Yu G, Fang W, Xia T, Chen Y, Gao Y, Jiao X, Huang S, Wang J, Li Z, Xie K - Oncotarget (2015)

Metformin treatment led to aberrant expression of invasion/migration-related genes(A) Heatmap representing hierarchical clustering of all genes that displayed a 1.5-fold or greater difference in transcript levels in metformin-treated BGC823 cells with a concentration of 20 mM compared to controls at days 0, 24 h, and 48 h (B) Significant gene ontology (GO) terms retrieved by clusters D–G. (C) Pearson correlation network of the metformin action course generated using the Spring-embedded algorithm in Cytoscape. Partial genes in enriched GO categories are represented in the network. Nodes represent genes, and connections represent correlation coefficient.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494971&req=5

Figure 5: Metformin treatment led to aberrant expression of invasion/migration-related genes(A) Heatmap representing hierarchical clustering of all genes that displayed a 1.5-fold or greater difference in transcript levels in metformin-treated BGC823 cells with a concentration of 20 mM compared to controls at days 0, 24 h, and 48 h (B) Significant gene ontology (GO) terms retrieved by clusters D–G. (C) Pearson correlation network of the metformin action course generated using the Spring-embedded algorithm in Cytoscape. Partial genes in enriched GO categories are represented in the network. Nodes represent genes, and connections represent correlation coefficient.
Mentions: In a global gene expression analysis, we found that 2025 genes were differentially expressed (1092 up-regulated and 933 down-regulated) at 24 h, while 503 were differentially expressed (280 up-regulated and 223 down-regulated) at 48 h (Figure 5A). These genes were clustered by expression pattern, yield several distinct clusters (such as, cell cycle, regulation of cellular process, regulation of biological process, metabolic process, etc.) (Figure 5B). According to gene expression patterns changed in the enriched GO categories, we created a network diagram to illustrate how these genes work over time by computing a Pearson correlation coefficient of all differentially expressed genes (Figure 5C). Our further analysis revealed that PTEN, a key inhibitor of Akt/mTOR pathway [20, 21], and CDKN1, a potent cyclin-dependent kinase inhibitor [22], were up-regulated at early stage after treated by metformin. However, genes associated with matrix degradation and tumor invasion displayed lower expression when treated with metformin persistently. These genes included DCN, CLDN1, FN1, MMP7, WFDC1, and UBD [23]. Strikingly, we observed that mRNA levels of DCN, MMP7, and WFDC1 didn't changed compared to control at earlier stage (24 h), but sharply reduced at later stage (48 h). Together, these data provided new evidences that sustained treatment of metformin leads to continuous damage of the ability of cell proliferation and invasion/migration.

Bottom Line: Also it enhanced cisplatin- or rapamycin-induced reduction of tumor growth as compared with treatment of either drug alone.In addition to activation of AMPK and suppression of the mTOR pathway, a series of increased and decreased genes expression were induced by metformin, including PTEN, MMP7, and FN1.We suggest that metformin could potentially be used for the treatment of gastric cancer especially in combination with cisplatin or rapamycin.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Changzheng Hospital, Shanghai 200070, China.

ABSTRACT
Here we showed that pAMPKα and PTEN were down-regulated and p-mTOR, p-S6, p-4EBP1, MMP7, and DCN1 were up-regulated in human gastric cancer tissue samples as compared to that in the noncancerous tissues. Metformin inhibited tumor growth in mice. Also it enhanced cisplatin- or rapamycin-induced reduction of tumor growth as compared with treatment of either drug alone. In addition to activation of AMPK and suppression of the mTOR pathway, a series of increased and decreased genes expression were induced by metformin, including PTEN, MMP7, and FN1. We suggest that metformin could potentially be used for the treatment of gastric cancer especially in combination with cisplatin or rapamycin.

No MeSH data available.


Related in: MedlinePlus