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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

Summary of metabolites and gene expression alteration in TCA cycle.(A) The expression analysis of genes involved in TCA cycle by using RT2 Profiler Array. (B) Altered metabolites in TCA cycle by metformin treatment. (C) The expression of genes in modulating the conversion between reduced and oxidized glutathione in microarray. 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. The dashed and black arrows in metabolic processes represent indirect or direct reactions. The metabolites alteration at 8, 24 and 48 h are labeled with red, green or blue arrow, respectively.
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f7: Summary of metabolites and gene expression alteration in TCA cycle.(A) The expression analysis of genes involved in TCA cycle by using RT2 Profiler Array. (B) Altered metabolites in TCA cycle by metformin treatment. (C) The expression of genes in modulating the conversion between reduced and oxidized glutathione in microarray. 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. The dashed and black arrows in metabolic processes represent indirect or direct reactions. The metabolites alteration at 8, 24 and 48 h are labeled with red, green or blue arrow, respectively.

Mentions: TCA cycle is the key process for tumor cells to generate ATP and intermediates for macromolecule biosynthesis (PNAS, 27). In this study, we found that about half of observed genes in TCA cycle was downregulated at con 24 h, and most of them was further reduced by metformin treatment (Fig. 7A). At metabolic level, several intermediates of TCA cycle were reduced in metformin-treated cells including citrate, malate, fumarate, and succinate. Meanwhile, the levels of some amino acids were significantly altered in metformin-treated cells such as increasing of tyrosine, phenylalanine, BCAAs, GABA, glutamate, glutamine and histidine at 8 h, but decreasing at 24 or 48 h (Fig. 7B). These amino acids play important roles in energy metabolism by conversion to intermediates of TCA cycle directly or indirectly. In addition to energy metabolism, the intracellular redox status is also important for tumor cell proliferation and survivor. In current study, we observed that 24 h treatment of metformin resulted in significant depletion of reduced glutathione and increasing of oxidized glutathione, suggesting the imbalance of intracellular redox status induced by metformin. Consistently, we found the expression of Glutathione peroxidase (GPX) 1 and glutathione reductase (GSR) genes were significantly upregulated by 24 h metformin treatment (Fig. 7C), which mediate the conversion between reduced- and oxidized- glutathione.


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)

Summary of metabolites and gene expression alteration in TCA cycle.(A) The expression analysis of genes involved in TCA cycle by using RT2 Profiler Array. (B) Altered metabolites in TCA cycle by metformin treatment. (C) The expression of genes in modulating the conversion between reduced and oxidized glutathione in microarray. 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. The dashed and black arrows in metabolic processes represent indirect or direct reactions. The metabolites alteration at 8, 24 and 48 h are labeled with red, green or blue arrow, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f7: Summary of metabolites and gene expression alteration in TCA cycle.(A) The expression analysis of genes involved in TCA cycle by using RT2 Profiler Array. (B) Altered metabolites in TCA cycle by metformin treatment. (C) The expression of genes in modulating the conversion between reduced and oxidized glutathione in microarray. 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. The dashed and black arrows in metabolic processes represent indirect or direct reactions. The metabolites alteration at 8, 24 and 48 h are labeled with red, green or blue arrow, respectively.
Mentions: TCA cycle is the key process for tumor cells to generate ATP and intermediates for macromolecule biosynthesis (PNAS, 27). In this study, we found that about half of observed genes in TCA cycle was downregulated at con 24 h, and most of them was further reduced by metformin treatment (Fig. 7A). At metabolic level, several intermediates of TCA cycle were reduced in metformin-treated cells including citrate, malate, fumarate, and succinate. Meanwhile, the levels of some amino acids were significantly altered in metformin-treated cells such as increasing of tyrosine, phenylalanine, BCAAs, GABA, glutamate, glutamine and histidine at 8 h, but decreasing at 24 or 48 h (Fig. 7B). These amino acids play important roles in energy metabolism by conversion to intermediates of TCA cycle directly or indirectly. In addition to energy metabolism, the intracellular redox status is also important for tumor cell proliferation and survivor. In current study, we observed that 24 h treatment of metformin resulted in significant depletion of reduced glutathione and increasing of oxidized glutathione, suggesting the imbalance of intracellular redox status induced by metformin. Consistently, we found the expression of Glutathione peroxidase (GPX) 1 and glutathione reductase (GSR) genes were significantly upregulated by 24 h metformin treatment (Fig. 7C), which mediate the conversion between reduced- and oxidized- glutathione.

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