Transcriptomic changes induced by mycophenolic acid in gastric cancer cells

Boying Dun, Ashok Kumar Sharma, Heng Xu, Haitao Liu, Shan Bai, Lingwen Zeng, Jin-Xiong She

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Background: Inhibition of inosine monophosphate dehydrogenase (IMPDH) by mycophenolic acid (MPA) can inhibit proliferation and induce apoptosis in cancer cells. This study investigated the underlying molecular mechanisms of MPA's anticancer activity. Methods: A gastric cancer cell line (AGS) was treated with MPA and gene expression at different time points was analyzed using Illumina whole genome microarrays and selected genes were confirmed by real-time RT-PCR. Results: Transcriptomic profiling identified 1070 genes with ≥2 fold changes and 85 genes with >4 fold alterations. The most significantly altered biological processes by MPA treatment include cell cycle, apoptosis, cell proliferation and migration. MPA treatment altered at least ten KEGG pathways, of which eight (p53 signaling, cell cycle, pathways in cancer, PPAR signaling, bladder cancer, protein processing in ER, small cell lung cancer and MAPK signaling) are cancer-related. Among the earliest cellular events induced by MPA is cell cycle arrest which may be caused by six molecular pathways: 1) up-regulation of cyclins (CCND1 and CCNE2) and down-regulation of CCNA2 and CCNB1, 2) down-regulation of cyclin-dependent kinases (CDK4 and CDK5); 3) inhibition of cell division related genes (CDC20, CDC25B and CDC25C) and other cell cycle related genes (MCM2, CENPE and PSRC1), 4) activation of p53, which activates the cyclin-dependent kinase inhibitors (CDKN1A), 5) impaired spindle checkpoint function and chromosome segregation (BUB1, BUB1B, BOP1, AURKA, AURKB, and FOXM1); and 6) reduction of availability of deoxyribonucleotides and therefore DNA synthesis through down-regulation of the RRM1 enzyme. Cell cycle arrest is followed by inhibition of cell proliferation, which is mainly attributable to the inhibition of the PI3K/AKT/mTOR pathway, and caspase-dependent apoptosis due to up-regulation of the p53 and FAS pathways. Conclusions: These results suggest that MPA has beneficial anticancer activity through diverse molecular pathways and biological processes.

Original languageEnglish (US)
Pages (from-to)28-42
Number of pages15
JournalAmerican Journal of Translational Research
Volume6
Issue number1
StatePublished - Jan 1 2014

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Mycophenolic Acid
Stomach Neoplasms
Cells
Genes
Biological Phenomena
Down-Regulation
Cyclin-Dependent Kinases
Apoptosis
Cell Cycle Checkpoints
Cell Cycle
Cell proliferation
Up-Regulation
Aurora Kinase A
Cell Proliferation
Deoxyribonucleotides
cdc Genes
Inosine Monophosphate
Neoplasms
Chromosome Segregation
Peroxisome Proliferator-Activated Receptors

Keywords

  • Drug repurposing
  • MPA
  • Microarray
  • Regulatory networks

ASJC Scopus subject areas

  • Molecular Medicine
  • Clinical Biochemistry
  • Cancer Research

Cite this

Transcriptomic changes induced by mycophenolic acid in gastric cancer cells. / Dun, Boying; Sharma, Ashok Kumar; Xu, Heng; Liu, Haitao; Bai, Shan; Zeng, Lingwen; She, Jin-Xiong.

In: American Journal of Translational Research, Vol. 6, No. 1, 01.01.2014, p. 28-42.

Research output: Contribution to journalArticle

Dun, Boying ; Sharma, Ashok Kumar ; Xu, Heng ; Liu, Haitao ; Bai, Shan ; Zeng, Lingwen ; She, Jin-Xiong. / Transcriptomic changes induced by mycophenolic acid in gastric cancer cells. In: American Journal of Translational Research. 2014 ; Vol. 6, No. 1. pp. 28-42.
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N2 - Background: Inhibition of inosine monophosphate dehydrogenase (IMPDH) by mycophenolic acid (MPA) can inhibit proliferation and induce apoptosis in cancer cells. This study investigated the underlying molecular mechanisms of MPA's anticancer activity. Methods: A gastric cancer cell line (AGS) was treated with MPA and gene expression at different time points was analyzed using Illumina whole genome microarrays and selected genes were confirmed by real-time RT-PCR. Results: Transcriptomic profiling identified 1070 genes with ≥2 fold changes and 85 genes with >4 fold alterations. The most significantly altered biological processes by MPA treatment include cell cycle, apoptosis, cell proliferation and migration. MPA treatment altered at least ten KEGG pathways, of which eight (p53 signaling, cell cycle, pathways in cancer, PPAR signaling, bladder cancer, protein processing in ER, small cell lung cancer and MAPK signaling) are cancer-related. Among the earliest cellular events induced by MPA is cell cycle arrest which may be caused by six molecular pathways: 1) up-regulation of cyclins (CCND1 and CCNE2) and down-regulation of CCNA2 and CCNB1, 2) down-regulation of cyclin-dependent kinases (CDK4 and CDK5); 3) inhibition of cell division related genes (CDC20, CDC25B and CDC25C) and other cell cycle related genes (MCM2, CENPE and PSRC1), 4) activation of p53, which activates the cyclin-dependent kinase inhibitors (CDKN1A), 5) impaired spindle checkpoint function and chromosome segregation (BUB1, BUB1B, BOP1, AURKA, AURKB, and FOXM1); and 6) reduction of availability of deoxyribonucleotides and therefore DNA synthesis through down-regulation of the RRM1 enzyme. Cell cycle arrest is followed by inhibition of cell proliferation, which is mainly attributable to the inhibition of the PI3K/AKT/mTOR pathway, and caspase-dependent apoptosis due to up-regulation of the p53 and FAS pathways. Conclusions: These results suggest that MPA has beneficial anticancer activity through diverse molecular pathways and biological processes.

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