P14ARF inhibits the growth of lung adenocarcinoma cells harbouring an EGFR L858R mutation by activating a STAT3-dependent pro-apoptotic signalling pathway

Abstract

Epidermal growth factor receptor (EGFR) stimulates proliferative and survival signals. Activating mutations of EGFR are involved in the aetiology and maintenance of the malignant phenotype of lung tumours. We previously described the frequent association of these mutations with the decreased expression of the p14ARF tumour suppressor, another common feature of lung cancer. Based on these data, we postulated that p14ARF could protect cells against untimely or excessive mitotic signals induced by mutant EGFR. In this study, we demonstrate that p14ARF promotes apoptosis in lung tumour cells harbouring the EGFR L858R mutation through the accumulation of phosphorylated signal transducer and activator of transcription 3 (STAT3) on Tyr 705 residue, which leads to Bcl-2 downregulation. Using siRNA against PTP-RT, the phosphatase that specifically targets Tyr 705 residue, we show that accumulation of pSTAT3-Tyr705 promotes EGFR L858R mutant cell death, thereby confirming the existence of a STAT3-dependent pro-apoptotic pathway in these cells. Finally, we show that the expression of the EGFR L858R mutant represses p14ARF expression and inhibits STAT3/Bcl-2 signalling. These results identify a novel link between the p14ARF and EGFR pathways and suggest that EGFR L858R counteracts the pro-apoptotic function of p14 ARF by downregulating its expression to promote carcinogenesis. © 2013 Macmillan Publishers Limited All rights reserved.