Camptothecin enhances c-Myc-mediated endoplasmic reticulum stress and leads to autophagy by activating Ca2+-mediated AMPK

Food Chem Toxicol. 2018 Nov;121:648-656. doi: 10.1016/j.fct.2018.09.057. Epub 2018 Sep 25.


Camptothecin (CPT) from Camptotheca acuminate was discovered for anticancer drugs, which targets topoisomease I. However, whether CPT regulates c-Myc expression has not been understood in endoplasmic reticulum (ER) stress and autophagy. In this study, we found that CPT enhanced c-Myc expression and that the transient knockdown of c-Myc abrogated reactive oxygen species (ROS) generation, which resulted in the accumulation of ER stress-regulating proteins, such as PERK, eIF2α, ATF4, and CHOP. Moreover, the transfection of eIF2α-targeted siRNA attenuated CPT-induced autophagy and decreased the levels of Beclin-1 and Atg7, which indicated that CPT upregulated ER stress-mediated autophagy. In addition, CPT phosphorylated AMPK in response to intracellular Ca2+ release. Ca2+ chelators, ethylene glycol tetraacetic acid and a CaMKII inhibitor, K252a, decreased CPT-induced Beclin-1 and Atg7, and downregulated AMPK phosphorylation, which suggested that CPT-induced Ca2+ release leads to the activation of autophagy through CaMKII-mediated AMPK phosphorylation. CPT also phosphorylated JNK and activated the DNA-binding activity of AP-1; furthermore, knockdown of JNK abolished the expression level of Beclin-1 and Atg7, which implied that the JNK-AP-1 pathway was a potent mediator of CPT-induced autophagy. Our findings indicated that CPT promoted c-Myc-mediated ER stress and ROS generation, which enhances autophagy via the Ca2+-AMPK and JNK-AP-1 pathways.

Keywords: Autophagy; Camptothecin; Endoplasmic reticulum stress; Reactive oxygen species; c-Myc.

MeSH terms

  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism*
  • Antineoplastic Agents, Phytogenic
  • Autophagy / drug effects*
  • Calcium / metabolism*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Endoplasmic Reticulum Stress / drug effects*
  • Gene Expression Regulation / drug effects
  • Humans
  • MAP Kinase Signaling System
  • Male
  • Prostatic Neoplasms / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Reactive Oxygen Species
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism
  • Transcription Factor CHOP / genetics
  • Transcription Factor CHOP / metabolism


  • Antineoplastic Agents, Phytogenic
  • DDIT3 protein, human
  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • Reactive Oxygen Species
  • Transcription Factor AP-1
  • Transcription Factor CHOP
  • AMP-Activated Protein Kinases
  • Calcium