Up-regulated EGF receptors undergo to rapid internalization and ubiquitin-dependent degradation in human cancer cells exposed to 8-Cl-cAMP

8-Cl-cAMP, a cAMP analogue that antagonizes type I cAMP-dependent protein k inase, is a novel anti-tumor agent presently under investigation in clinica l trials, Herein we report the effects of this agent on epidermal growth fa ctor receptor expression and degradation in human KB cancer cells. Exposure to 10 mu M 8-Cl-cAMP for 48 h induced a 65% increase in epidermal growth f actor receptor surface expression while the receptor synthesis was 22-fold enhanced. Analysis of epidermal growth factor-dependent receptor internaliz ation in 8-Cl-cAMP-treated cells showed a higher endocytosis rate as well a s an accelerated degradation which occurred together with an increased rece ptor ubiquitination. The enhanced degradation of epidermal growth factor re ceptor correlated with the lack of epidermal growth factor-induced prolifer ation and mitogen-activated protein kinase stimulation. The disregulation o f epidermal growth factor receptor internalization and ubiquitin-dependent degradation could underlay a new mechanism of the anti-tumor activity of 8- Cl-cAMP suggesting its combination with agents that disrupt epidermal growt h factor receptor signalling. (C) 1999 Federation of European Biochemical S ocieties.