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

Abstract

SummaryThe 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-CI-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 growthpromoting activity of EGF was completely abolished when EGF treatment was performed in combination with 8-CI-cAMP. The inhibition of the EGF-induced proliferation by 8-CI-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.

The Platelet-Activating Factor Receptor Activates the Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase and Induces Proliferation of Epidermal Cells through an Epidermal Growth Factor-Receptor-Dependent Pathway

“…The results of our study indicate that PAF has mitogenic actions in epidermal cells and confirm previous findings that EGF induced proliferation in KB cells (Budillon et al, 1999). In fact, exposing KBP cells to EGF or CPAF significantly increased cell proliferation.…”

“…Since ERK activation is frequently part of the mitogenic signal transduction pathway, we sought to determine whether the PAF-R-induced cellular proliferation. The potent mitogenic stimulator EGF was used as a positive control for proliferation (Ishii et al, 1997;Budillon et al, 1999;Sato et al, 1999). Exposure to 20 ng/ml EGF for 48 h significantly increased the proliferation of both KBP and KBM cells ( Fig.…”

Chemoprevention of lung cancer by tea

“…Research suggests that human and hamster adenocarcinomas of Clara cell lineage are regulated via activation of cAMP [70,71,78,79], and may be promoted by consumption of green tea. In contrast, human and murine pulmonary adenocarcinomas of alveolar type II cell lineage may be inhibited by the blocking of Raf-1 by cAMP accumulation [80][81][82][83][84][85] caused by green tea.…”

Neuroendocrine lung carcinogenesis in hamsters is inhibited by green tea or theophylline while the development of adenocarcinomas is promoted: implications for chemoprevention in smokers

“…Our research suggests that the growth of human and hamster pulmonary adenocarcinomas of Clara cell lineage is regulated by ␤-adrenergic receptors via activation of cAMP and release of AA [25,26,28,46]. By contrast, published evidence suggests that the AA cascade is activated in human and murine pulmonary adenocarcinomas of alveolar type II cell lineage by the epidermal growth factor receptor (EGFr) pathway and a PKC-mediated pathway [39,[47][48][49][50][51]. A major concern with respect to lung cancer prevention is the fact that these pathways appear to be antagonistic at the level of cAMP/PKA.…”

“…An identical growth-regulating pathway has been identified in cultured hamster pulmonary neuroendocrine cells [21,23], considered the cells of origin of the neuroendocrine lung tumors induced in hyperoxic hamsters by NNK. Among the components of this signal transduction pathway, Raf-1 has been shown to be blocked by cAMP and the resulting activation of protein kinase A in several cell systems [2,39,40]. The chemopreventive effects of green tea observed in our neuroendocrine lung cancer model were therefore likely caused by the inhibiting effects of caffeine and theophylline on Raf-1.…”