Naringin induces endoplasmic reticulum stress-mediated apoptosis, inhibits β-catenin pathway and arrests cell cycle in cervical cancer cells

Acta Biochim Pol. 2020 Apr 28;67(2):181-188. doi: 10.18388/abp.2020_5182.

Abstract

Naringin is a promising anticancer bioflavonoid phytochemical, mainly extracted from citrus fruits. This study evaluates the antiproliferative effect and the cell death mechanism induced by naringin on cervical cancer (CC) cells. Our results demonstrated that naringin exerts significant inhibition in cell viability and exhibits IC50 value 745, 764, 793 µM against C33A, SiHa, and HeLa cells respectively. Annexin V FITC and immunoblotting analysis reveal significant apoptosis induction in cells exposed to higher doses naringin. Mechanistically, naringin induces endoplasmic reticulum (ER) stress-associated cell killing in CC cells. Naringin increases the protein expression of ER stress sensors, phosphorylates eIF2α by and activates apoptosis-associated protein CHOP and other associated proapoptotic proteins (PARP1 and caspase-3). Intriguingly, pre-treatment with of ER stress inhibitor (salubrinal), reverses the apoptotic effect exerted by naringin. Additionally, the naringin abrogates the β-catenin pathway by decreasing the protein expression as well as phosphorylation of β-catenin (Ser576) and GSK-3β (Ser9) and simultaneously triggers cell cycle arrest at a G0/G1 phase by increasing the expression of cell cycle checkpoint proteins p21/cip and p27/kip. Naringin induces ER stress-mediated apoptosis and simultaneously abrogates Wnt/β-catenin signaling which eventually triggers the arrest of the cell cycle at a G0/G1 phase in CC cells.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Cell Survival / drug effects
  • Drugs, Chinese Herbal / pharmacology*
  • Endoplasmic Reticulum Stress / drug effects*
  • Female
  • Flavanones / pharmacology*
  • G1 Phase Cell Cycle Checkpoints / drug effects*
  • HeLa Cells
  • Humans
  • Phosphorylation / drug effects
  • Polypodiaceae / chemistry
  • Uterine Cervical Neoplasms / drug therapy*
  • Uterine Cervical Neoplasms / metabolism
  • Uterine Cervical Neoplasms / pathology
  • Wnt Signaling Pathway / drug effects*
  • beta Catenin / antagonists & inhibitors*
  • beta Catenin / metabolism

Substances

  • Antineoplastic Agents
  • Drugs, Chinese Herbal
  • Flavanones
  • beta Catenin
  • naringin