A synthetic chalcone, 2'-hydroxy-2,3,5'-trimethoxychalcone triggers unfolded protein response-mediated apoptosis in breast cancer cells

Cancer Lett. 2016 Mar 1;372(1):1-9. doi: 10.1016/j.canlet.2015.12.017. Epub 2015 Dec 29.

Abstract

The primary aim of this study was to find novel chemopreventive agents effective against breast cancer. Endoplasmic reticulum (ER) stress can induce apoptosis through the unfolded protein response (UPR). 2'-Hydroxy-2,3,5'-trimethoxychalcone (DK143) is a synthetic flavonoid derivative. The present study provides evidence supporting the role of the UPR in mediating the apoptotic effect of DK143. Treatment with DK143 triggered apoptosis through the activation of the caspase pathway in MDA-MB-231 breast cancer cells without affecting viability of MCF10A non-transformed breast epithelial cells. Further analysis revealed that DK143 produced reactive oxygen species (ROS) in MDA-MB-231 cells, but not in MCF10A cells, and upregulated the expression of ER stress sensors, including GRP78/BiP, IRE1α, CHOP, and Bim in MDA-MB-231 cells. In addition, UPR-related transcription factors, XBP-1 and CHOP, were activated by DK143. Moreover, silencing of IRE1α or CHOP by corresponding siRNA molecules attenuated DK143-induced apoptosis. Furthermore, DK143 suppressed mouse tumor growth in vivo. These results demonstrate that promoting ER stress in breast cancer cells via UPR induction might be a promising strategy for developing new chemotherapeutic or chemopreventive agents for breast cancer.

Keywords: 2'-Hydroxy-2,3,5'-trimethoxychalcone; Apoptosis; Breast cancer; Caspase; Reactive oxygen species; Unfolded protein response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins / metabolism
  • Bcl-2-Like Protein 11
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Caspases / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Chalcones / chemical synthesis
  • Chalcones / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design
  • Endoplasmic Reticulum / drug effects*
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum / pathology
  • Endoplasmic Reticulum Chaperone BiP
  • Endoribonucleases / genetics
  • Endoribonucleases / metabolism
  • Female
  • Heat-Shock Proteins / metabolism
  • Humans
  • Membrane Proteins / metabolism
  • Mice, Inbred BALB C
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • RNA Interference
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects
  • Time Factors
  • Transcription Factor CHOP / genetics
  • Transcription Factor CHOP / metabolism
  • Transfection
  • Tumor Burden / drug effects
  • Unfolded Protein Response / drug effects*

Substances

  • 2'-hydroxy-2,3,5'-trimethoxychalcone
  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Chalcones
  • DDIT3 protein, human
  • Endoplasmic Reticulum Chaperone BiP
  • HSPA5 protein, human
  • Heat-Shock Proteins
  • Hspa5 protein, mouse
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Reactive Oxygen Species
  • Transcription Factor CHOP
  • ERN1 protein, human
  • Protein Serine-Threonine Kinases
  • Endoribonucleases
  • Caspases