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Clock and ATF4 transcription system regulates drug resistance in human cancer cell lines

T Igarashi1, H Izumi, T Uchiumi

  • 1Department of Molecular Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan.

Oncogene
|February 14, 2007
PubMed

Insights

The circadian transcription factor Clock regulates activating transcription factor 4 (ATF4), impacting cellular drug resistance. Clock and ATF4 overexpression promote multidrug resistance, suggesting a role in redox systems for cancer therapy.

Area of Science:

  • * Molecular Biology
  • * Cancer Research
  • * Chronobiology

Background:

  • * Cellular drug resistance mechanisms are known, but regulation remains unclear.
  • * Activating transcription factor 4 (ATF4) is upregulated in cisplatin-resistant cells.
  • * The circadian transcription factor Clock influences various gene expressions, including those related to tumor growth.

Purpose of the Study:

  • * To investigate the novel relationship between the circadian transcription factor Clock and cellular drug resistance.
  • * To determine if ATF4 is a direct target of Clock.
  • * To explore the role of the Clock-ATF4 system in multidrug resistance and glutathione metabolism.

Main Methods:

  • * Analysis of Clock and ATF4 expression in cisplatin-resistant cells.
  • * Investigation of Clock's regulatory role on ATF4.
  • * Assessment of Clock and ATF4 downregulation effects on drug sensitivity in A549 cells.
  • * Microarray analysis to identify genes regulated by ATF4 in glutathione metabolism.

Main Results:

  • * Clock is overexpressed in cisplatin-resistant cells and directly targets ATF4.
  • * Downregulation of Clock or ATF4 increases sensitivity to cisplatin and etoposide in A549 cells.
  • * ATF4 overexpression confers multidrug resistance and elevates intracellular glutathione.
  • * ATF4 knockdown downregulates genes involved in glutathione metabolism.

Conclusions:

  • * The Clock and ATF4 transcription system plays a significant role in multidrug resistance via the glutathione-dependent redox system.
  • * Targeting the Clock-controlled redox system may offer new therapeutic strategies for oxidative stress-associated disorders, including cancer.
  • * Understanding the circadian regulation of redox systems could be crucial for developing effective cancer chronotherapy.

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