The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Mutant p53-Notch1 Signaling Axis Is Involved in Curcumin-Induced Apoptosis of Breast Cancer Cells

  • Bae, Yun-Hee (Department of Dental Pharmacology, School of Dentistry, Yangsan Campus of Pusan National University) ;
  • Ryu, Jong Hyo (Department of Dental Pharmacology, School of Dentistry, Yangsan Campus of Pusan National University) ;
  • Park, Hyun-Joo (Department of Oral Physiology, School of Dentistry, Yangsan Campus of Pusan National University) ;
  • Kim, Kwang Rok (Korea Research Institute of Chemical Technology) ;
  • Wee, Hee-Jun (College of Pharmacy, Seoul National University) ;
  • Lee, Ok-Hee (Severance Integrative Research Institute for Cerebral and Cardiovascular Diseases, Yonsei University Health System) ;
  • Jang, Hye-Ock (Department of Dental Pharmacology, School of Dentistry, Yangsan Campus of Pusan National University) ;
  • Bae, Moon-Kyoung (Department of Oral Physiology, School of Dentistry, Yangsan Campus of Pusan National University) ;
  • Kim, Kyu-Won (College of Pharmacy, Seoul National University) ;
  • Bae, Soo-Kyung (Department of Dental Pharmacology, School of Dentistry, Yangsan Campus of Pusan National University)
  • Received : 2013.02.26
  • Accepted : 2013.05.28
  • Published : 2013.08.30
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Abstract

Notch1 has been reported to be highly expressed in triple-negative and other subtypes of breast cancer. Mutant p53 (R280K) is overexpressed in MDA-MB-231 triple-negative human breast cancer cells. The present study aimed to determine whether the mutant p53 can be a potent transcriptional activator of the Notch1 in MDA-MB-231 cells, and explore the role of this mutant p53-Notch1 axis in curcumin-induced apoptosis. We found that curcumin treatment resulted in an induction of apoptosis in MDA-MB-231 cells, together with downregulation of Notch1 and its downstream target, Hes1. This reduction in Notch1 expression was determined to be due to the decreased activity of endogenous mutant p53. We confirmed the suppressive effect of curcumin on Notch1 transcription by performing a Notch1 promoter-driven reporter assay and identified a putative p53-binding site in the Notch1 promoter by EMSA and chromatin immunoprecipitation analysis. Overexpression of mutant p53 increased Notch1 promoter activity, whereas knockdown of mutant p53 by small interfering RNA suppressed Notch1 expression, leading to the induction of cellular apoptosis. Moreover, curcumin-induced apoptosis was further enhanced by the knockdown of Notch1 or mutant p53, but it was decreased by the overexpression of active Notch1. Taken together, our results demonstrate, for the first time, that Notch1 is a transcriptional target of mutant p53 in breast cancer cells and suggest that the targeting of mutant p53 and/or Notch1 may be combined with a chemotherapeutic strategy to improve the response of breast cancer cells to curcumin.

Keywords

References

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