8-Cl-cAMP antagonizes mitogen-activated protein kinase activation and cell growth stimulation induced by epidermal growth factor

A. Budillon, E. Di Gennaro, M. Caraglia, D. Barbarulo, A. Abbruzzese, P. Tagliaferri

Research output: Contribution to journalArticlepeer-review

Abstract

The growth factor-activated mitogenic pathways are often disregulated in tumour cells and, therefore, they can provide specific molecular targets for novel anti-tumour approaches. 8-Chloro-cAMP (8-Cl-cAMP), a synthetic cAMP analogue, is a novel anti-tumour agent that has recently undergone clinical evaluation. We investigated the effects of 8-Cl-cAMP on the epidermal growth factor (EGF)/EGF receptor (EGF-R) signalling in human epidermoid cancer KB cells, which are responsive to the mitogenic stimulus of EGF. We found that the growth-promoting activity of EGF was completely abolished when EGF treatment was performed in combination with 8-Cl-cAMP. The inhibition of the EGF-induced proliferation by 8-Cl-cAMP was paralleled by the blockade of the EGF-stimulated activation of mitogen-activated protein kinases (MAPK), ERK-1 and ERK-2. Conversely, we found an increase of EGF-R expression and EGF-R tyrosine phosphorylation when KB cells were growth inhibited by 8-Cl-cAMP. Moreover, the activity of Raf-1 and MEK-1 protein kinases, the activators upstream MAPK in the phosphorylation cascade induced by EGF, was not modified in 8-Cl-cAMP-treated cells. We concluded that the impairment of KB cell response to EGF, induced by 8-Cl-cAMP, resides in the specific inhibition of MAPK/ERKs activity while the function of the upstream elements in the EGF-R signalling is preserved.

Original languageEnglish
Pages (from-to)1134-1141
Number of pages8
JournalBritish Journal of Cancer
Volume81
Issue number7
Publication statusPublished - 1999

Keywords

  • cAMP analogue
  • EGF
  • MAPK
  • Protein kinase A

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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