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

The growth factor-activated mitogenic pathways are often disregulated in tu mour cells and, therefore, they can provide specific molecular targets for novel anti-tumour approaches. 8-Chloro-cAMP (8-Cl-cAMP), a synthetic cAMP a nalogue, is a novel anti-tumour agent that has recently undergone clinical evaluation, We investigated the effects of 8-Cl-cAMP on the epidermal growt h factor (EGF)/EGF receptor (EGF-R) signalling in human epidermoid cancer K B cells, which are responsive to the mitogenic stimulus of EGF, We found th at the growth-promoting activity of EGF was completely abolished when EGF t reatment 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 t he EGF-stimulated activation of mitogen-activated protein kinases (MAPK), E RK-1 and ERK-2. Conversely, we found an increase of EGF-R expression and EG F-R tyrosine phosphorylation when KB cells were growth inhibited by 8-Cl-cA MP, Moreover, the activity of Raf-1 and MEK-1 protein kinases, the activato rs upstream MAPK in the phosphorylation cascade induced by EGF, was not mod ified in 8-Cl-cAMP-treated cells. We concluded that the impairment of KB ce ll response to EGF, induced by 8-Cl-cAMP, resides in the specific inhibitio n of MAPK/ERKs activity while the function of the upstream elements in the EGF-R signalling is preserved. (C) 1999 Cancer Research Campaign.