Differential mTOR and PI3K Pathway Activation in Human Bronchial Carcinoids

Bronchial carcinoids (BCs) are tumors originating from endocrine cells dispersed in the respiratory epithelium. BC can be divided into typical (TBC) and atypical (ABC). TBC are in general less aggressive, smaller, and much less likely to metastasize as compared to ABC. mTOR has a central role in regulating cell growth, metabolism, and apoptosis. A differential mTOR activation in TBC vs. ABC has been previously demonstrated, suggesting that mTOR pathway profile might predict the response to mTOR-targeted therapies. Our aim is to evaluate the effects of Everolimus, an mTOR inhibitor, and NVP-BEZ 235, a dual mTOR/PI3K inhibitor, on human BC cell lines. NCI H720 (ABC) and NCI H727 (TBC) cells were treated with Everolimus or NVP-BEZ 235. Cell viability, caspase 3/7 activities and cell cycle progression were evaluated after 72 h. We found that 50 nM Everolimus inhibits cell viability by -40% in NCI H720 cells and by -10% in NCI H727 cells (P<0.01); 50 nM NVP-BEZ 235 has similar effects on NCI H727, but has greater effects on NCI H720 (-50%; P<0.01). Everolimus does not induce apoptosis, but promotes an accumulation in G1/G0 (+10% in NCI H727 and +25% in NCI H720 cells vs. ct). NVP-BEZ 235 does not promote apoptosis in NCI H727, but induces this process in NCI H720 (+50%), and causes G1/G0 accumulation in both NCI H727 (+10%) and NCIH720 (+35%), with a parallel decrease in cyclin D1 levels, in GSK3β phosphorilation and in ERK1/2 activation. In addition, mTOR expression is greater, at both protein and mRNA levels, in NCI H720 cells as compared to NCI H727 (1.5 fold).These data demonstrate that mTOR and PI3K pathway are differentially activated in human BCs cell lines, depending on stage (TBC vs. ABC) and mTOR expression levels. These data support previous findings showing that Everolimus reduces cell viability of selected human primary coltures of BC. Moreover, NVP-BEZ 235 could have a role in the medical treatment of ABCs.