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Structure-Guided Design and Development of Novel Cyclophilin A Inhibitors and Ganoderiol-F Derivatives: An In-Silico Approach
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Structure-Guided Design and Development of Novel Cyclophilin A Inhibitors and Ganoderiol-F Derivatives: An In-Silico Approach

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The anti-invasive activity of cyclooxygenase inhibitors is regulated by the transcription factor ATF3 (activating

Frank G Bottone1, Yuseok Moon, Jong Sik Kim

  • 1Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, NIH, P.O. Box 12233, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709, USA.

Molecular Cancer Therapeutics
|May 18, 2005
PubMed

Insights

Activating transcription factor 3 (ATF3) is upregulated by nonsteroidal anti-inflammatory drugs (NSAIDs). Overexpressing ATF3 inhibits colorectal cancer cell invasion and tumor growth, revealing a novel anti-invasive mechanism for NSAIDs.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Nonsteroidal anti-inflammatory drugs (NSAIDs) exhibit chemopreventive properties by modulating gene expression.
  • Activating transcription factor 3 (ATF3) is a key transcription factor implicated in cell proliferation, apoptosis, and invasion.
  • ATF3 expression is notably reduced in human colorectal tumors compared to adjacent normal tissues.

Purpose of the Study:

  • To investigate the role of ATF3 in colorectal cancer.
  • To determine if ATF3 mediates the anti-cancer effects of NSAIDs.
  • To elucidate the mechanism by which ATF3 influences cancer cell invasion and tumor growth.

Main Methods:

  • Microarray analysis to identify NSAID-modulated genes.
  • Overexpression of ATF3 in sense and antisense orientations in HCT-116 cells.
  • In vitro focus formation assays and in vivo mouse tumor xenograft studies.
  • Real-time reverse transcription-PCR to validate gene expression changes related to invasion and metastasis.

Main Results:

  • NSAIDs, troglitazone, diallyl disulfide, and resveratrol up-regulated ATF3 mRNA and protein expression in colorectal cancer cells.
  • Overexpression of ATF3 significantly reduced focus formation in vitro and decreased tumor xenograft size by 54% in vivo.
  • ATF3 overexpression inhibited cell invasion, while antisense ATF3 expression promoted invasion, similar to sulindac sulfide treatment.
  • Microarray and real-time PCR identified several invasion and metastasis-related genes regulated by ATF3 and modulated by sulindac sulfide.

Conclusions:

  • ATF3 plays a critical role in suppressing colorectal cancer cell invasion and tumor growth.
  • NSAIDs, including sulindac sulfide, exert anti-invasive effects partly through the up-regulation of ATF3.
  • ATF3 represents a novel molecular target and mechanism underlying the chemopreventive activity of NSAIDs in colorectal cancer.

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