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ROS inhibit autophagy by downregulating ULK1 mediated by the phosphorylation of p53 in selenite-treated NB4 cells

Y Ci1, K Shi1, J An1

  • 1State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences and School of Basic Medicine, Department of Biochemistry and Molecular Biology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.

Cell Death & Disease
|November 28, 2014
PubMed

Insights

Selenium compounds inhibit protective autophagy in cancer cells by reducing ULK1 expression via the p70S6K/p53 pathway, a finding confirmed in vivo.

Area of Science:

  • Cellular Biology
  • Cancer Research
  • Molecular Oncology

Background:

  • Reactive oxygen species (ROS) regulate cellular functions.
  • Selenite, an anti-tumour agent, induces apoptosis via ROS.
  • The role of ROS in autophagy regulation by selenite is not fully understood.

Purpose of the Study:

  • To investigate the effect of ROS on autophagy in selenite-treated NB4 cells.
  • To elucidate the molecular mechanism by which ROS affects autophagy initiation.
  • To validate the identified molecular axis in a preclinical cancer model.

Main Methods:

  • Cell culture of NB4 cells.
  • Analysis of autophagy markers and ULK1 expression.
  • Western blotting to detect p-p53 (S392) and p70S6K.
  • Chromatin immunoprecipitation assays to assess p53 binding to the ULK1 promoter.
  • In vivo studies using a mouse xenograft model.

Main Results:

  • Selenite-induced ROS inhibited autophagy in NB4 cells by decreasing ULK1 expression.
  • Phosphorylated p53 (p-p53 at S392), promoted by p70S6K, was found to bind the ULK1 promoter.
  • This interaction modulated ULK1 expression, thereby inhibiting autophagy.
  • The p70S6K/p53/ULK1 pathway alterations were confirmed in a mouse tumour model.

Conclusions:

  • ROS generated by selenite inhibit autophagy by downregulating the p70S6K/p53/ULK1 signaling axis.
  • This mechanism contributes to the anti-tumour effects of selenite.
  • Targeting this pathway could offer novel therapeutic strategies in cancer treatment.

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