L-Ascorbic Acid Inhibits Breast Cancer Growth by Inducing IRE/JNK/CHOP-Related Endoplasmic Reticulum Stress-Mediated p62/SQSTM1 Accumulation in the Nucleus

Nutrients. 2020 May 8;12(5):1351. doi: 10.3390/nu12051351.


Anticancer effects of L-ascorbic acid (Vitamin C, L-AA) have been reported in various types of cancers. L-AA intake reduces breast cancer recurrence and mortality; however, the role of L-AA in the treatment of breast cancer remains poorly understood. In this study, we investigated the effect and mechanism action of L-AA on breast cancer growth. L-AA inhibited the growth of breast cancer cells by inducing apoptotic cell death at the evaluated treatment concentrations without affecting normal cells. Moreover, L-AA induces autophagosome formation via regulation of mammalian target of rapamycin (mTOR), Beclin1, and autophagy-related genes (ATGs) and increased autophagic flux. Notably, we observed that L-AA increased p62/SQSTM1 (sequestosome 1) protein levels. Accumulation of p62 protein in cancer cells in response to stress has been reported, but its role in cancer regulation remains controversial. Here, we demonstrated that L-AA-induced p62 accumulation is related to L-AA-induced breast cancer growth inhibition. Furthermore, L-AA induced endoplasmic reticulum (ER) stress via the IRE-JNK-CHOP (inositol-requiring endonuclease-c-Jun N-terminal kinase-C/EBP homologous protein) signaling pathways, which increased the nuclear levels of p62/SQSTM1. These findings provide evidence that L-AA-induced ER stress could be crucial for p62 accumulation-dependent cell death, and L-AA can be useful in breast cancer treatment.

Keywords: ER stress; IRE–JNK–CHOP signaling; L-ascorbic acid; autophagy; breast cancer; p62/SQSTM1.

MeSH terms

  • Ascorbic Acid / pharmacology*
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Nucleus / metabolism*
  • Endoplasmic Reticulum Stress / drug effects*
  • Endoribonucleases / metabolism
  • Female
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • RNA-Binding Proteins / metabolism
  • Sequestosome-1 Protein / metabolism
  • Signal Transduction / drug effects*
  • Transcription Factor CHOP / metabolism


  • DDIT3 protein, human
  • P62 protein, human
  • RNA-Binding Proteins
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Transcription Factor CHOP
  • JNK Mitogen-Activated Protein Kinases
  • Endoribonucleases
  • Ascorbic Acid