Inhibiting autophagy with chloroquine enhances the anti-tumor effect of high-LET carbon ions via ER stress-related apoptosis

Med Oncol. 2017 Feb;34(2):25. doi: 10.1007/s12032-017-0883-8. Epub 2017 Jan 9.

Abstract

Energetic carbon ions (CI) offer great advantages over conventional radiations such as X- or γ-rays in cancer radiotherapy. High linear energy transfer (LET) CI can induce both endoplasmic reticulum (ER) stress and autophagy in tumor cells under certain circumstances. The molecular connection between ER stress and autophagy in tumor exposed to high-LET radiation and how these two pathways influence the therapeutic effect against tumor remain poorly understood. In this work, we studied the impact of autophagy and apoptosis induced by ER stress following high-LET CI radiation on the radiosensitivity of S180 cells both in vitro and in vivo. In the in vitro experiment, X-rays were also used as a reference radiation. Our results documented that the combination of CI radiation with chloroquine (CQ), a special autophagy inhibitor, produced more pronounced proliferation suppression in S180 cells and xenograft tumors. Co-treatment with CI radiation and CQ could block autophagy through the IRE1/JNK/Beclin-1 axis and enhance apoptotic cell death via the activation of C/EBP homologous protein (CHOP) by the IRE1 pathway rather than PERK in vitro and in vivo. Thus, our study indicates that inhibiting autophagy might be a promising therapeutic strategy in CI radiotherapy via aggravating the ER stress-related apoptosis.

Keywords: Apoptosis; Autophagy; CHOP; Chloroquine; ER stress; High-LET radiation.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / radiation effects
  • Autophagy / drug effects
  • Autophagy / radiation effects
  • Carbon*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / radiation effects
  • Chloroquine / pharmacology*
  • Endoplasmic Reticulum Stress / drug effects*
  • Endoplasmic Reticulum Stress / radiation effects*
  • Female
  • Flow Cytometry
  • Heavy Ion Radiotherapy / methods*
  • Heavy Ions
  • Membrane Proteins / metabolism
  • Mice
  • Protein Serine-Threonine Kinases / metabolism
  • Random Allocation
  • Sarcoma / drug therapy*
  • Sarcoma / metabolism
  • Sarcoma / pathology
  • Sarcoma / radiotherapy*
  • Signal Transduction / drug effects
  • Signal Transduction / radiation effects
  • Transcription Factor CHOP / metabolism

Substances

  • Ddit3 protein, mouse
  • Membrane Proteins
  • Transcription Factor CHOP
  • Carbon
  • Chloroquine
  • Ern2 protein, mouse
  • Protein Serine-Threonine Kinases