Activation of the MAPK11/12/13/14 (p38 MAPK) pathway regulates the transcription of autophagy genes in response to oxidative stress induced by a novel copper complex in HeLa cells

Autophagy. 2014 Jul;10(7):1285-300. doi: 10.4161/auto.28789. Epub 2014 May 13.


Transition metal copper (Cu) can exist in oxidized or reduced states in cells, leading to cytotoxicity in cancer cells through oxidative stress. Recently, copper complexes are emerging as a new class of anticancer compounds. Here, we report that a novel anticancer copper complex (HYF127c/Cu) induces oxidative stress-dependent cell death in cancer cells. Further, transcriptional analysis revealed that oxidative stress elicits broad transcriptional changes of genes, in which autophagy-related genes are significantly changed in HYF127c/Cu-treated cells. Consistently, autophagy was induced in HYF127c/Cu-treated cells and inhibitors of autophagy promoted cell death induced by HYF127c/Cu. Further analysis identified that the MAPK11/12/13/14 (formerly known as p38 MAPK) pathway was also activated in HYF127c/Cu-treated cells. Meanwhile, the MAPK11/12/13/14 inhibitor SB203580 downregulated autophagy by inhibiting the transcription of the autophagy genes MAP1LC3B, BAG3, and HSPA1A, and promoted HYF127c/Cu-induced cell death. These data suggest that copper-induced oxidative stress will induce protective autophagy through transcriptional regulation of autophagy genes by activation of the MAPK11/12/13/14 pathway in HeLa cells.

Keywords: HYF127c/Cu; MAPK11; MAPK12; MAPK13; MAPK14; autophagy; copper; oxidative stress; p38 mitogen-activated protein kinase; transcription.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Autophagy / drug effects
  • Autophagy / genetics*
  • Cell Proliferation / drug effects
  • Copper / chemistry
  • Copper / pharmacology*
  • Down-Regulation / drug effects
  • Enzyme Activation / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • HeLa Cells
  • Humans
  • Imidazoles / pharmacology
  • MAP Kinase Signaling System / drug effects*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Neoplasms / ultrastructure
  • Oxidative Stress / drug effects
  • Oxidative Stress / genetics*
  • Pyridines / pharmacology
  • Sequence Analysis, RNA
  • Stress, Physiological / drug effects
  • Transcription, Genetic / drug effects*
  • Vacuoles / drug effects
  • Vacuoles / metabolism
  • Vacuoles / pathology
  • Vacuoles / ultrastructure
  • p38 Mitogen-Activated Protein Kinases


  • Imidazoles
  • Neoplasm Proteins
  • Pyridines
  • Copper
  • p38 Mitogen-Activated Protein Kinases
  • SB 203580