Neuroendocrine (NE) phenotypes characterize a spectrum of lung
tumors, including low-grade typical and intermediate-grade atypical
carcinoid, high-grade large-cell NE
carcinoma and
small cell lung carcinoma. Currently, no effective treatments are available to cure NE lung
tumors, demanding identification of
biological features specific to these
tumors. Here, we report that autophagy has an important role for NE lung
tumor cell proliferation and survival. We found that the expression levels of the autophagy marker LC3 are relatively high in a panel of lung tumor cell lines expressing high levels of
neuron-specific enolase (NSE), a key NE marker in lung
tumors. In response to
bafilomycin A1 and
chloroquine, NE lung
tumor cells exhibited cytotoxicity whereas non-NE lung
tumor cells exhibited cytostasis, indicating a distinct role of autophagy for NE lung
tumor cell survival. Intriguingly, in certain NE lung tumor cell lines, the levels of processed LC3 (LC3-II) were inversely correlated with AKT activity. When AKT activity was inhibited using AKTi or
MK2206, the levels of LC3-II and SQSTM1/p62 were increased. In contrast,
torin 1,
rapamycin or mTOR knockdown increased p62 levels, suggesting that these two pathways have opposing effects on autophagy in certain NE lung
tumors. Moreover, inhibition of one pathway resulted in reduced activity of the other, suggesting that these two pathways crosstalk in the
tumors. These results suggest that NE lung
tumor cells share a common feature of autophagy and are more sensitive to autophagy inhibition than non-NE lung
tumor cells.