Mitogen-activated protein kinase (MAPK) activation by butylated hydroxytoluene hydroperoxide: Implications for cellular survival and tumor promotion

Kathryn Z. Guyton, Myriam Gorospe, Thomas W Kensler, Nikki J. Holbrook

Research output: Contribution to journalArticle

Abstract

The mitogen-activated protein kinase (MAPK) cascade plays an important role in carcinogenic development. Herein, we show that the skin tumor promoter butylated hydroxytoluene hydroperoxide (BHTOOH) stimulates a rapid and potent (14- to 20-fold) activation of extracellular signal-regulated kinase (ERK) in vivo and in cultured mouse keratinocytes. BHTOOH also moderately (5-fold) activated c-jun-N-terminal kinase and 38-kDa MAPK- related protein in these same cells. N-acetylcysteine and o-phenanthroline abolished ERK activation by BHTOOH, consistent with a requirement for metal- dependent formation of reactive intermediates. Indeed, 4-CD3-BHTOOH, an analogue that generates less of the metabolite BHT-quinone methide (2,6-di- tert-butyl-4-methylene-2,5-cyclohexadienone) and fewer tumors in vivo, accordingly exhibited diminished potency for activating ERK. ERK activation by BHTOOH was inhibited by suramin, and by expression of dominant-negative Ras-N-17 in PC12 cells, suggesting overlap between the pathways for BHTOOH and growth factor signaling. Induction of MAPK-dependent genes c-fos and MAPK phosphatase-1 by BHTOOH was also blocked by Ras-N-17 expression. Moreover, expression of Ras-N-17 or kinase-defective MAPK kinase (MEK) diminished cell survival following BHTOOH exposure. Similarly, pretreatment with suramin or the MEK inhibitor PD098059 also potentiated the toxicity of BHTOOH. On the other band, expression of constitutively active MEK enhanced cell survival. Thus, we demonstrate that the MAPK cascade is critical to the cellular response to BHTOOH. This study suggests a functional role for MAPK activation in tumor promotion stimulated by oxidants and other agents.

Original languageEnglish (US)
Pages (from-to)3480-3485
Number of pages6
JournalCancer Research
Volume56
Issue number15
StatePublished - Aug 1 1996

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Butylated Hydroxytoluene
Mitogen-Activated Protein Kinases
Hydrogen Peroxide
Extracellular Signal-Regulated MAP Kinases
Neoplasms
Mitogen-Activated Protein Kinase Kinases
Suramin
Cell Survival
Mitogen-Activated Protein Kinase Phosphatases
Dual Specificity Phosphatase 1
2,6-di-tert-butyl-4-hydroperoxy-4-methyl-2,5-cyclohexadienone
MAP Kinase Kinase Kinases
fos Genes
JNK Mitogen-Activated Protein Kinases
PC12 Cells
Acetylcysteine
Keratinocytes
Oxidants
Carcinogens
Intercellular Signaling Peptides and Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Mitogen-activated protein kinase (MAPK) activation by butylated hydroxytoluene hydroperoxide : Implications for cellular survival and tumor promotion. / Guyton, Kathryn Z.; Gorospe, Myriam; Kensler, Thomas W; Holbrook, Nikki J.

In: Cancer Research, Vol. 56, No. 15, 01.08.1996, p. 3480-3485.

Research output: Contribution to journalArticle

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