N-(4-hydroxyphenyl)retinamide-induced apoptosis triggered by reactive oxygen species is mediated by activation of MAPKs in head and neck squamous carcinoma cells

Oncogene. 2006 May 4;25(19):2785-94. doi: 10.1038/sj.onc.1209303.


N-(4-hydroxyphenyl)retinamide (4HPR), a synthetic retinoid effective in cancer chemoprevention and therapy, is thought to act via apoptosis induction resulting from increased reactive oxygen species (ROS) generation. As ROS can activate MAP kinases and protein kinase C (PKC), we examined the role of such enzymes in 4HPR-induced apoptosis in HNSCC UMSCC22B cells. 4HPR increased ROS level within 1 h and induced activation of caspase 3 and PARP cleavage within 24 h. Activation of MKK3/6 and MKK4, JNK, p38 and ERK was detected between 6 and 12 h, increased up to 24 h and preceded apoptosis. 4HPR-induced activation of these kinases was abrogated by the antioxidants BHA and vitamin C. SP600125, a JNK inhibitor, suppressed 4HPR-induced c-Jun phosphorylation, cytochrome c release from mitochondria and apoptosis. Suppression of JNK1 and JNK2 using siRNA decreased, whereas overexpression of wild type-JNK1 enhanced 4HPR-induced apoptosis. PD169316, a p38, inhibitor suppressed phosphorylation of Hsp27 and apoptosis. PD98059, an MEK1/2 inhibitor, also suppressed ERK1/2 activation and apoptosis induced by 4HPR. Likewise, PKC inhibitor GF109203X suppressed ERK and p38 phosphorylation and PARP cleavage. These data indicate that 4HPR-induced apoptosis is triggered by ROS increase, leading to the activation of the mitogen-activated protein serine/threonine kinases JNK, p38, PKC and ERK, and subsequent apoptosis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anticarcinogenic Agents / pharmacology*
  • Antioxidants / pharmacology
  • Apoptosis / drug effects*
  • Carcinoma, Squamous Cell / enzymology*
  • Carcinoma, Squamous Cell / pathology
  • Caspase 3
  • Caspases / metabolism
  • Cytochromes c / metabolism
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Fenretinide / pharmacology*
  • Head and Neck Neoplasms / enzymology*
  • Head and Neck Neoplasms / pathology
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Mitogen-Activated Protein Kinases / metabolism*
  • Phosphorylation / drug effects
  • Poly(ADP-ribose) Polymerases / metabolism
  • Protein Kinase C / metabolism
  • Proto-Oncogene Proteins c-jun / metabolism
  • Reactive Oxygen Species / metabolism*
  • Tumor Cells, Cultured


  • Anticarcinogenic Agents
  • Antioxidants
  • Enzyme Inhibitors
  • Proto-Oncogene Proteins c-jun
  • Reactive Oxygen Species
  • Fenretinide
  • Cytochromes c
  • Poly(ADP-ribose) Polymerases
  • Protein Kinase C
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • CASP3 protein, human
  • Caspase 3
  • Caspases