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RING1 Inhibition Has a Cell-Specific Antitumoral Role by Promoting Autophagy in Endometrial Cancer Cells

Aleksandra Szustka1, Karolina Kozal1,2, Anna Krześlak3

  • 1University of Lodz, Faculty of Biology and Environmental Protection, Department of Cytobiochemistry.

Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology
|January 14, 2024
PubMed
Abstract

Insights

Inhibition of RING1A/B proteins impacts autophagy and apoptosis in endometrial cancer. Combining the RING1 inhibitor PRT4165 with autophagy inhibitors showed reduced anticancer effectiveness, suggesting alternative strategies are needed.

Area of Science:

  • Cancer Biology
  • Molecular Oncology
  • Epigenetics

Background:

  • Histone modifications regulate gene expression and autophagy in cancer.
  • RING1A/B proteins of Polycomb repressive complex 1 (PRC1) monoubiquitylate histone H2A, influencing gene expression.
  • Autophagy plays a critical role in cancer progression and treatment resistance.

Purpose of the Study:

  • To investigate the effect of RING1A/B protein inhibition on autophagy in endometrial cancer.
  • To evaluate the anticancer efficacy of the RING1 inhibitor PRT4165, alone and in combination with autophagy inhibitors.
  • To explore the role of glucose concentration and cell type in PRT4165 response.

Main Methods:

  • Analysis of autophagy gene and protein expression in HEC-1A and Ishikawa endometrial cancer cells under varying glucose conditions and PRT4165 treatment.
  • Determination of IC50 and combination index (CI) to assess PRT4165 efficacy with autophagy inhibitors (HCQ, Lys05).
  • Flow cytometry to quantify apoptosis induction following treatment.

Main Results:

  • RING1 inhibition significantly altered autophagy gene and protein expression in endometrial cancer cells, with effects varying by glucose concentration and cell type.
  • PRT4165 treatment impacted autophagy markers and induced apoptosis.
  • The combination of PRT4165 with autophagy inhibitors (HCQ, Lys05) demonstrated reduced anticancer effectiveness compared to PRT4165 monotherapy.

Conclusions:

  • RING proteins are crucial regulators of autophagy and apoptosis in endometrial cancer.
  • The combination of PRT4165 with current autophagy inhibitors is not a promising anticancer strategy.
  • Further research is needed to identify more effective combinations of PRT4165 with novel autophagy modulators.
Keywords:
Ring1 ; Autophagy ; Inhibitors ; Endometrial cancer cells

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