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Metformin suppressed the proliferation of LoVo cells and induced a time-dependent metabolic and transcriptional alteration.

He J, Wang K, Zheng N, Qiu Y, Xie G, Su M, Jia W, Li H - Sci Rep (2015)

Bottom Line: An obvious time-dependent metabolic alteration was observed from 8 to 48 h, prior to the reduction of cell viability.Meanwhile, the transcirptomic profile revealed 134 and 3061 differentially expressed genes at 8 and 24 h by metformin.Altogether, our current data indicate that metformin suppressed the proliferation of LoVo cells, which may be due to the modulation on cell energy metabolism at both metabolic and transcriptional levels in a time-dependent way.

View Article: PubMed Central - PubMed

Affiliation: Center for Chinese Medical Therapy and Systems Biology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.

ABSTRACT
Metformin is a widely used anti-diabetic drug with potential anti-tumor activity. However, little is known about its global metabolic and transcriptional impacts on tumor cells. In current study, we performed a metabolic profiling on human-derived colon cancer LoVo cells treated by 10 mM metformin for 8, 24 and 48 h. An obvious time-dependent metabolic alteration was observed from 8 to 48 h, prior to the reduction of cell viability. A total of 47, 45 and 66 differential metabolites were identified between control and metformin-treated cells at three time points. Most of the metabolites were up-regulated at 8 h, but down-regulated at 24 and 48 h by metformin. These metabolites were mainly involved in carbohydrates, lipids, amino acids, vitamins and nucleotides metabolism pathways. Meanwhile, the transcirptomic profile revealed 134 and 3061 differentially expressed genes at 8 and 24 h by metformin. In addition to the cancer signaling pathways, expression of genes involved in cell energy metabolism pathways was significantly altered, which were further validated with genes in glucose metabolism pathway. Altogether, our current data indicate that metformin suppressed the proliferation of LoVo cells, which may be due to the modulation on cell energy metabolism at both metabolic and transcriptional levels in a time-dependent way.

No MeSH data available.


Related in: MedlinePlus

The expression analysis of genes involved in pentose phosphate pathway and regulation on glucose and glycogen metabolism.(A) The expression of genes in pentose phosphate pathway. (B) The expression of genes in regulation on glucose and glycogen metabolism. Data are means ± S.E.M. of triplicates for each group. *indicates P < 0.05 compared to Con 8 h group, #P < 0.05 compared to Con 24 h group with Student’s t test.
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f6: The expression analysis of genes involved in pentose phosphate pathway and regulation on glucose and glycogen metabolism.(A) The expression of genes in pentose phosphate pathway. (B) The expression of genes in regulation on glucose and glycogen metabolism. Data are means ± S.E.M. of triplicates for each group. *indicates P < 0.05 compared to Con 8 h group, #P < 0.05 compared to Con 24 h group with Student’s t test.

Mentions: To further characterize the time-dependent modulation on energy metabolism by metformin, we analyzed the expression of 84 genes in glucose metabolism pathways including genes in glycolysis, gluconeogenesis, regulation on glucose and gluconeogenesis, and TCA cycle processes. In general, the expression panel of the observed 81 genes (three genes were excluded due to very low expression level in all samples) in glucose metabolism pathways was consistent with the transcriptomic profiling. In glycolysis and gluconeogenesis pathway, a lot of genes were upregulated with culture time in control cells, but most of them were downregulated by metformin treatment, especially at 24 h (Fig. 5A,B). In gluconeogenesis pathway, although the expression of both phosphoenolpyruvate carboxykinase 1 (PCK1) and phosphoenolpyruvate carboxykinase 2 (PCK2) was upregulated with culture time in control cells, metformin treatment further stimulated the expression of PCK1, but suppressed PCK2 at 24 h (Fig. 5B). The transcriptional alteration was consistent with the observations of metabolic changes induced by metformin, in which several metabolites in glycolysis and gluconeogenesis processes were reduced in metformin-treated cells including pyruvate, lactate, glyceraldehyde-3P, alanine, and aspartic acid (Fig. 5C,D). Pentose phosphate pathway is an important metabolic pathway to generate NADPH and pentoses paralleling to glycolysis. In current study, we observed that most of the genes involved in pentose phosphate pathway was downregulated or unchanged at Con 24 h group compared to Con 8 h group, except for two upregulated genes at Con 24 h that is phosphoribosyl pyrophosphate synthetase 2 (PRPS2) and phosphoribosyl pyrophosphate synthetase 1-like 1 (PRPS1L1) which catalyze the synthesis of purines and pyrimidines, as well as ribonucleoside monophosphates. Although, 8 h metformin treatment did not induce obviously transcriptional changes among observed genes in pentose phosphate pathway, the expression panel of genes in Met 24 h group was similar to that of Con 24 h, except for the dramatic suppression of PRPS2, PRPS1L1, and hexose-6-phosphate dehydrogenase (H6PD) genes resulted from 24 h metformin treatment (Fig. 6A). In addition, genes which are regulators of glycolysis and gluconeogenesis pathways were also analyzed. We observed that most genes were not changed at Met 8 h group, but were significantly suppressed at Met 24 h group compared to Con 8 h or Con 24 h group respectively (Fig. 6B).


Metformin suppressed the proliferation of LoVo cells and induced a time-dependent metabolic and transcriptional alteration.

He J, Wang K, Zheng N, Qiu Y, Xie G, Su M, Jia W, Li H - Sci Rep (2015)

The expression analysis of genes involved in pentose phosphate pathway and regulation on glucose and glycogen metabolism.(A) The expression of genes in pentose phosphate pathway. (B) The expression of genes in regulation on glucose and glycogen metabolism. Data are means ± S.E.M. of triplicates for each group. *indicates P < 0.05 compared to Con 8 h group, #P < 0.05 compared to Con 24 h group with Student’s t test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663508&req=5

f6: The expression analysis of genes involved in pentose phosphate pathway and regulation on glucose and glycogen metabolism.(A) The expression of genes in pentose phosphate pathway. (B) The expression of genes in regulation on glucose and glycogen metabolism. Data are means ± S.E.M. of triplicates for each group. *indicates P < 0.05 compared to Con 8 h group, #P < 0.05 compared to Con 24 h group with Student’s t test.
Mentions: To further characterize the time-dependent modulation on energy metabolism by metformin, we analyzed the expression of 84 genes in glucose metabolism pathways including genes in glycolysis, gluconeogenesis, regulation on glucose and gluconeogenesis, and TCA cycle processes. In general, the expression panel of the observed 81 genes (three genes were excluded due to very low expression level in all samples) in glucose metabolism pathways was consistent with the transcriptomic profiling. In glycolysis and gluconeogenesis pathway, a lot of genes were upregulated with culture time in control cells, but most of them were downregulated by metformin treatment, especially at 24 h (Fig. 5A,B). In gluconeogenesis pathway, although the expression of both phosphoenolpyruvate carboxykinase 1 (PCK1) and phosphoenolpyruvate carboxykinase 2 (PCK2) was upregulated with culture time in control cells, metformin treatment further stimulated the expression of PCK1, but suppressed PCK2 at 24 h (Fig. 5B). The transcriptional alteration was consistent with the observations of metabolic changes induced by metformin, in which several metabolites in glycolysis and gluconeogenesis processes were reduced in metformin-treated cells including pyruvate, lactate, glyceraldehyde-3P, alanine, and aspartic acid (Fig. 5C,D). Pentose phosphate pathway is an important metabolic pathway to generate NADPH and pentoses paralleling to glycolysis. In current study, we observed that most of the genes involved in pentose phosphate pathway was downregulated or unchanged at Con 24 h group compared to Con 8 h group, except for two upregulated genes at Con 24 h that is phosphoribosyl pyrophosphate synthetase 2 (PRPS2) and phosphoribosyl pyrophosphate synthetase 1-like 1 (PRPS1L1) which catalyze the synthesis of purines and pyrimidines, as well as ribonucleoside monophosphates. Although, 8 h metformin treatment did not induce obviously transcriptional changes among observed genes in pentose phosphate pathway, the expression panel of genes in Met 24 h group was similar to that of Con 24 h, except for the dramatic suppression of PRPS2, PRPS1L1, and hexose-6-phosphate dehydrogenase (H6PD) genes resulted from 24 h metformin treatment (Fig. 6A). In addition, genes which are regulators of glycolysis and gluconeogenesis pathways were also analyzed. We observed that most genes were not changed at Met 8 h group, but were significantly suppressed at Met 24 h group compared to Con 8 h or Con 24 h group respectively (Fig. 6B).

Bottom Line: An obvious time-dependent metabolic alteration was observed from 8 to 48 h, prior to the reduction of cell viability.Meanwhile, the transcirptomic profile revealed 134 and 3061 differentially expressed genes at 8 and 24 h by metformin.Altogether, our current data indicate that metformin suppressed the proliferation of LoVo cells, which may be due to the modulation on cell energy metabolism at both metabolic and transcriptional levels in a time-dependent way.

View Article: PubMed Central - PubMed

Affiliation: Center for Chinese Medical Therapy and Systems Biology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.

ABSTRACT
Metformin is a widely used anti-diabetic drug with potential anti-tumor activity. However, little is known about its global metabolic and transcriptional impacts on tumor cells. In current study, we performed a metabolic profiling on human-derived colon cancer LoVo cells treated by 10 mM metformin for 8, 24 and 48 h. An obvious time-dependent metabolic alteration was observed from 8 to 48 h, prior to the reduction of cell viability. A total of 47, 45 and 66 differential metabolites were identified between control and metformin-treated cells at three time points. Most of the metabolites were up-regulated at 8 h, but down-regulated at 24 and 48 h by metformin. These metabolites were mainly involved in carbohydrates, lipids, amino acids, vitamins and nucleotides metabolism pathways. Meanwhile, the transcirptomic profile revealed 134 and 3061 differentially expressed genes at 8 and 24 h by metformin. In addition to the cancer signaling pathways, expression of genes involved in cell energy metabolism pathways was significantly altered, which were further validated with genes in glucose metabolism pathway. Altogether, our current data indicate that metformin suppressed the proliferation of LoVo cells, which may be due to the modulation on cell energy metabolism at both metabolic and transcriptional levels in a time-dependent way.

No MeSH data available.


Related in: MedlinePlus