Decitabine induces G2/M cell cycle arrest by suppressing p38/NF-κB signaling in human renal clear cell carcinoma.

Abstract

OBJECTIVE:

The anti-neoplastic effects of decitabine, an inhibitor of DNA promoter methylation, are beneficial for the treatment of renal cell carcinoma (RCC); however, the mechanism of action of decitabine is unclear. We analyzed gene expression profiling and identified specific pathways altered by decitabine in RCC cells.

METHODS:

Four human RCC cell lines (ACHN, Caki-1, Caki-1, and A498) were used in this study; growth suppression of RCC cells by decitabine was analyzed using the WST-1 assay. Apoptosis and cell cycle arrest were examined using flow cytometric analysis. Gene expression of RCC cells induced by decitabine was evaluated with cDNA microarray, and potential biological pathways were selected using Ingenuity Pathway Analysis. The activity of the p38-NF-κB pathway regulated by decitabine was confirmed by Western blotting.

RESULTS:

Decitabine suppresses the proliferation of RCC cells in vitro. Although decitabine did not significantly induce apoptosis, decitabine caused cell cycle arrest at G2/M in a dose-dependent manner. Gene expression regulated by decitabine in RCC cells was investigated using microarray analysis. Ubiquitin carboxyl terminal hydrolase 1 (UCHL1), interferon inducible protein 27 (IFI27), and cell division cycle-associated 2 (CDCA2) may be involved in growth suppression of RCC cells by decitabine. The phosphorylation of p38-NF-κB pathway was suppressed by decitabine in RCC cells.

CONCLUSIONS:

We investigated gene expression profiling and pathways modulated by decitabine in RCC cells. Decitabine was shown to suppress the growth of RCC cells via G2/M cell cycle arrest and the p38-NF-κB signaling pathway may play a role in the anti-neoplastic effect of decitabine in RCC cells.

• Authors: Donghao Shang, Tiandong Han, Xiuhong Xu, Yuting Liu
• Journal: International journal of clinical and experimental pathology (Int J Clin Exp Pathol) Vol. 8 Issue 9 Pg. 11140-8 ( 2015) ISSN: 1936-2625 [Electronic] United States
• PMID: 26617834 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• CDCA2 protein, human
• Carrier Proteins
• Cell Cycle Proteins
• IFI27 protein, human
• Membrane Proteins
• NF-kappa B
• Nuclear Proteins
• UCHL1 protein, human
• Decitabine
• p38 Mitogen-Activated Protein Kinases
• Ubiquitin Thiolesterase
• Azacitidine

Topics

• Antimetabolites, Antineoplastic (pharmacology)
• Apoptosis (drug effects)
• Azacitidine (analogs & derivatives, pharmacology)
• Carcinoma, Renal Cell (drug therapy, enzymology, genetics, pathology)
• Carrier Proteins (genetics, metabolism)
• Cell Cycle Proteins (genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Decitabine
• Dose-Response Relationship, Drug
• Down-Regulation
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Gene Expression Profiling (methods)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Kidney Neoplasms (drug therapy, enzymology, genetics, pathology)
• Membrane Proteins (genetics, metabolism)
• NF-kappa B (metabolism)
• Nuclear Proteins (genetics, metabolism)
• Oligonucleotide Array Sequence Analysis
• Signal Transduction (drug effects)
• Ubiquitin Thiolesterase (genetics, metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)