Editors' ChoiceCancer

Inhibiting Autophagy by Phosphorylation

Sci. Signal.  24 Sep 2013:
Vol. 6, Issue 294, pp. ec226
DOI: 10.1126/scisignal.2004748

Hyperactivation of epidermal growth factor (EGF) signaling by genetic mutation or amplification of the EGF receptor tyrosine kinase (EGFR) is a hallmark of many cancers, including non–small cell lung carcinomas (NSCLC). Wei et al. identified the autophagy-related protein Beclin 1 as a target of EGFR in NSCLC. EGF stimulation of NSCLC cells with endogenous, wild-type EGFR or overexpression of mutant active EGFR (L858R or Δ746-750) in cells with low endogenous EGFR promoted EGFR binding to and phosphorylation of Beclin 1, inhibited the binding of Beclin 1 to and the activity of the proautophagy kinase VPS34, enhanced the binding of Beclin 1 to antiautophagy proteins Rubicon and Bcl-2, and reduced starvation-induced autophagy. Drugs that inhibit EGFR tyrosine kinase activity (TKIs), such as erlotinib, limit NSCLC growth in patients, but many patients develop resistance. Treating TKI-sensitive, but not TKI-resistant, NSCLC cells with erlotinib inhibited EGFR binding to and phosphorylation of Beclin 1, altered the interactions of Beclin 1 with other autophagy-related proteins, and induced autophagy. Cultured NSCLC cells expressing a phosphomimetic-mutant Beclin 1 (Beclin 1 EEE) were resistant to TKI-induced autophagy, and these cells exhibited reduced basal autophagy and accelerated tumor growth when xenografted into mice. In contrast, xenografts of NSCLC cells expressing Beclin 1 with mutations that prevented phosphorylation showed delayed tumor growth. Beclin 1 EEE–expressing xenografts counterintuitively showed enhanced apoptosis but also enhanced cell proliferation and characteristics of malignancy. Inducible overexpression of Beclin EEE in established xenografts revealed that inhibition of TKI-induced autophagy led to TKI resistance. These findings shed light on the paradoxical notion that autophagy-related proteins limit tumor initiation yet contribute to malignancy by allowing cancer cells to survive in the stressful tumor microenvironment (see Fantin and Abraham).

Y. Wei, Z. Zou, N. Becker, M. Anderson, R. Sumpter, G. Xiao, L. Kinch, P. Koduru, C. S. Christudass, R. W. Veltri, N. V. Grishin, M. Peyton, J. Minna, G. Bhagat, B. Levine, EGFR-mediated Beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance. Cell 154, 1269–1284 (2013).[PubMed]

V. R. Fantin, R. T. Abraham, Self-eating limits EGFR-dependent tumor growth. Cell 154, 1184–1186 (2013).[PubMed]