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Transcriptomic analysis of pancreatic cancer cells in response to metformin and aspirin: an implication of synergy.

Yue W, Wang T, Zachariah E, Lin Y, Yang CS, Xu Q, DiPaola RS, Tan XL - Sci Rep (2015)

Bottom Line: Of the top 10 genes (fold-change > 10, P < 10(-10)) regulated by metformin plus aspirin, PCDH18, CCL2, RASL11A, FAM111B and BMP5 were down-regulated ≥ 20-fold, while NGFR, NPTX1, C7orf57, MRPL23AS1 and UNC5B were up-regulated ≥ 10-fold.Ingenuity Pathway Analysis (IPA) revealed that the pathways, "cholesterol biosynthesis", "cell cycle: G1/S checkpoint regulation", and "axonal guidance signaling" were the most statistically significant pathways modulated by metformin plus aspirin.Although the results need further functional validation, these data provide the first evidence for the synergistic action between metformin and aspirin in modulating the transcriptional profile of pancreatic cancer cells.

View Article: PubMed Central - PubMed

Affiliation: Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901.

ABSTRACT
Metformin and aspirin have been studied extensively as cancer preventative and therapeutic agents. However, the underlying molecular mechanisms for the inhibitory effects of pancreatic cancer development remain undefined. To gain further insight into their biological function in pancreatic cancer, we conducted a transcriptomic analysis using RNA sequencing to assess the differential gene expression induced by metformin (5 mM) and aspirin (2 mM), alone or in combination, after treatment of PANC-1 cells for 48 hours. Compared to an untreated control, metformin down-regulated 58 genes and up-regulated 91 genes, aspirin down-regulated 12 genes only, while metformin plus aspirin down-regulated 656 genes and up-regulated 449 genes (fold-change > 2, P < 10(-5)). Of the top 10 genes (fold-change > 10, P < 10(-10)) regulated by metformin plus aspirin, PCDH18, CCL2, RASL11A, FAM111B and BMP5 were down-regulated ≥ 20-fold, while NGFR, NPTX1, C7orf57, MRPL23AS1 and UNC5B were up-regulated ≥ 10-fold. Ingenuity Pathway Analysis (IPA) revealed that the pathways, "cholesterol biosynthesis", "cell cycle: G1/S checkpoint regulation", and "axonal guidance signaling" were the most statistically significant pathways modulated by metformin plus aspirin. Although the results need further functional validation, these data provide the first evidence for the synergistic action between metformin and aspirin in modulating the transcriptional profile of pancreatic cancer cells.

No MeSH data available.


Related in: MedlinePlus

Overview of genes regulated by metformin and aspirin.(A,B) Venn diagrams comparing the down-regulated (A) and up-regulated (B) genes after treatments of metformin and aspirin, alone or the combination. (C) The clustering heat map of 16 samples based on the 150 top differentially expressed genes across 4 groups (untreated control, metformin, aspirin and metformin plus aspirin). Each column is labeled with different colors according to the sample type. Met, metformin; Asp, aspirin
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f1: Overview of genes regulated by metformin and aspirin.(A,B) Venn diagrams comparing the down-regulated (A) and up-regulated (B) genes after treatments of metformin and aspirin, alone or the combination. (C) The clustering heat map of 16 samples based on the 150 top differentially expressed genes across 4 groups (untreated control, metformin, aspirin and metformin plus aspirin). Each column is labeled with different colors according to the sample type. Met, metformin; Asp, aspirin

Mentions: To determine the impact of metformin and aspirin on the whole transcriptome, we compared the global gene expression profiles of untreated PANC-1 cells to those treated by metformin, aspirin, or a combination. We detected and quantified 11,551 unique genes, and compared the gene expression profiles of all three drug-treated samples to the untreated sample. Differentially expressed genes were identified by arbitrarily using a 2.0-fold-change cut-off value (P value < 1 × 10−5) compared to the untreated PANC-1 cells. We identified 149 differentially expressed genes (58 down-regulated and 91 up-regulated) from the metformin treated cells and 12 genes (all down-regulated) from the aspirin treated cells. Moreover, we identified 1,105 genes (656 down-regulated and 449 up-regulated) that have significantly different expression levels in the metformin-aspirin-combination treated cells. Of the genes downregulated by metformin alone, 79.3% (46/58) were also down-regulated by the combination of metformin and aspirin (Fig. 1A), while 58.2% (53/91) of the up-regulated genes by metformin also appeared in the subset of up-regulated genes by the combination (Fig. 1B). However, the genes regulated by aspirin alone did not show much commonality with those by metformin alone or the combination of metformin and aspirin. Only 25.0% (3/12) and 8.3% (1/12) of the down-regulated genes by aspirin were also down-regulated in metformin treated cells and metformin-aspirin treated cells, respectively (Fig. 1A). As shown in Fig. 2C, the clustering of top differentially expressed genes showed clearly distinguishable patterns across four conditions.


Transcriptomic analysis of pancreatic cancer cells in response to metformin and aspirin: an implication of synergy.

Yue W, Wang T, Zachariah E, Lin Y, Yang CS, Xu Q, DiPaola RS, Tan XL - Sci Rep (2015)

Overview of genes regulated by metformin and aspirin.(A,B) Venn diagrams comparing the down-regulated (A) and up-regulated (B) genes after treatments of metformin and aspirin, alone or the combination. (C) The clustering heat map of 16 samples based on the 150 top differentially expressed genes across 4 groups (untreated control, metformin, aspirin and metformin plus aspirin). Each column is labeled with different colors according to the sample type. Met, metformin; Asp, aspirin
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4543968&req=5

f1: Overview of genes regulated by metformin and aspirin.(A,B) Venn diagrams comparing the down-regulated (A) and up-regulated (B) genes after treatments of metformin and aspirin, alone or the combination. (C) The clustering heat map of 16 samples based on the 150 top differentially expressed genes across 4 groups (untreated control, metformin, aspirin and metformin plus aspirin). Each column is labeled with different colors according to the sample type. Met, metformin; Asp, aspirin
Mentions: To determine the impact of metformin and aspirin on the whole transcriptome, we compared the global gene expression profiles of untreated PANC-1 cells to those treated by metformin, aspirin, or a combination. We detected and quantified 11,551 unique genes, and compared the gene expression profiles of all three drug-treated samples to the untreated sample. Differentially expressed genes were identified by arbitrarily using a 2.0-fold-change cut-off value (P value < 1 × 10−5) compared to the untreated PANC-1 cells. We identified 149 differentially expressed genes (58 down-regulated and 91 up-regulated) from the metformin treated cells and 12 genes (all down-regulated) from the aspirin treated cells. Moreover, we identified 1,105 genes (656 down-regulated and 449 up-regulated) that have significantly different expression levels in the metformin-aspirin-combination treated cells. Of the genes downregulated by metformin alone, 79.3% (46/58) were also down-regulated by the combination of metformin and aspirin (Fig. 1A), while 58.2% (53/91) of the up-regulated genes by metformin also appeared in the subset of up-regulated genes by the combination (Fig. 1B). However, the genes regulated by aspirin alone did not show much commonality with those by metformin alone or the combination of metformin and aspirin. Only 25.0% (3/12) and 8.3% (1/12) of the down-regulated genes by aspirin were also down-regulated in metformin treated cells and metformin-aspirin treated cells, respectively (Fig. 1A). As shown in Fig. 2C, the clustering of top differentially expressed genes showed clearly distinguishable patterns across four conditions.

Bottom Line: Of the top 10 genes (fold-change > 10, P < 10(-10)) regulated by metformin plus aspirin, PCDH18, CCL2, RASL11A, FAM111B and BMP5 were down-regulated ≥ 20-fold, while NGFR, NPTX1, C7orf57, MRPL23AS1 and UNC5B were up-regulated ≥ 10-fold.Ingenuity Pathway Analysis (IPA) revealed that the pathways, "cholesterol biosynthesis", "cell cycle: G1/S checkpoint regulation", and "axonal guidance signaling" were the most statistically significant pathways modulated by metformin plus aspirin.Although the results need further functional validation, these data provide the first evidence for the synergistic action between metformin and aspirin in modulating the transcriptional profile of pancreatic cancer cells.

View Article: PubMed Central - PubMed

Affiliation: Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901.

ABSTRACT
Metformin and aspirin have been studied extensively as cancer preventative and therapeutic agents. However, the underlying molecular mechanisms for the inhibitory effects of pancreatic cancer development remain undefined. To gain further insight into their biological function in pancreatic cancer, we conducted a transcriptomic analysis using RNA sequencing to assess the differential gene expression induced by metformin (5 mM) and aspirin (2 mM), alone or in combination, after treatment of PANC-1 cells for 48 hours. Compared to an untreated control, metformin down-regulated 58 genes and up-regulated 91 genes, aspirin down-regulated 12 genes only, while metformin plus aspirin down-regulated 656 genes and up-regulated 449 genes (fold-change > 2, P < 10(-5)). Of the top 10 genes (fold-change > 10, P < 10(-10)) regulated by metformin plus aspirin, PCDH18, CCL2, RASL11A, FAM111B and BMP5 were down-regulated ≥ 20-fold, while NGFR, NPTX1, C7orf57, MRPL23AS1 and UNC5B were up-regulated ≥ 10-fold. Ingenuity Pathway Analysis (IPA) revealed that the pathways, "cholesterol biosynthesis", "cell cycle: G1/S checkpoint regulation", and "axonal guidance signaling" were the most statistically significant pathways modulated by metformin plus aspirin. Although the results need further functional validation, these data provide the first evidence for the synergistic action between metformin and aspirin in modulating the transcriptional profile of pancreatic cancer cells.

No MeSH data available.


Related in: MedlinePlus