RESUMO
Non-small cell lung carcinoma (NSCLC) is the leading type of lung cancer; smoking is a documented risk factor. Nicotinic acetylcholine receptor (nAChR)-mediated intracellular signaling in response to nicotine has recently been implicated in the growth regulation of NSCLC. In the current study nude mice carrying xenografts of the human lung NSCLC cell lines NCI-H322 or NCI-H441 were used as animal models. Nicotine administration and gamma aminobutyric acid (GABA) treatment lasted for 30 days. Catecholamines, cortisol, GABA, and cAMP were analyzed in blood and tumor tissues by immunoassays. Expression of nicotinic receptors and effector proteins in the xenografts was assessed by Western blotting. Our data indicate that nicotine stimulated the growth of NSCLC xenografts via modulation of nAChR upregulation and activation of cAMP signaling. The nicotine-treated group showed an enhanced level of stress neurotransmitters and second messenger cAMP in serum, blood cellular fraction, and xenograft tissues. Activation of critical proteins in the oncogenic pathway, including CREB, ERK, Akt, and Src, and upregulation of α-4 and α-7 subunits of nAChR provided mechanistic insight for the observed stimulatory effect of nicotine. Interestingly, GABA, being an antagonist to cAMP signaling, showed a promising intervention by reversing the stimulatory effect of nicotine on cancer growth and all signaling pathways. GABA has potential to lower the risk of NSCLC among smokers and could be used to enhance the clinical outcome of standard cancer intervention strategies.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Nicotina/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto , Ácido gama-Aminobutírico/farmacologia , Animais , Divisão Celular/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Nus , Nicotina/farmacologia , Receptores Nicotínicos/efeitos dos fármacosRESUMO
Smoking is a risk factor for lung cancer, chronic obstructive pulmonary disease, chronic bronchitis and asthma. The chronic lung diseases are also a predisposing factor for the development of lung cancer. Glucocorticoids are used for the management of chronic lung diseases because of their anti-inflammatory activity. These drugs also have anti-tumourigenic effects in mouse models of lung cancer. Glucocorticoids are frequently used as co-treatment with cancer therapy. Using the human pulmonary adenocarcinoma (PAC) cell line NCI-H322 with features of bronchiolar Clara cells, and immortalised human small airway epithelial cells, our data show that the glucocorticoid dexamethasone increased cell proliferation in MTT assays in a PKA-dependent manner. Dexamethasone significantly increased intracellular cAMP in direct immunoassays. Immunoblot analysis revealed increased phosphorylation of ERK1/2 and of the transcription factor CREB in response to dexamethasone. These data suggest that glucocorticoids could have tumour promoting activity on a sub-set of human PAC.