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Akt inhibition promotes autophagy and sensitizes PTEN-null tumors to lysosomotropic agents
Correspondence to Kui Lin: klin{at}gene.com
Although Akt is known as a survival kinase, inhibitors of the phosphatidylinositol 3-kinase (PI3K)–Akt pathway do not always induce substantial apoptosis. We show that silencing Akt1 alone, or any combination of Akt isoforms, can suppress the growth of tumors established from phosphatase and tensin homologue–null human cancer cells. Although these findings indicate that Akt is essential for tumor maintenance, most tumors eventually rebound. Akt knockdown or inactivation with small molecule inhibitors did not induce significant apoptosis but rather markedly increased autophagy. Further treatment with the lysosomotropic agent chloroquine caused accumulation of abnormal autophagolysosomes and reactive oxygen species, leading to accelerated cell death in vitro and complete tumor remission in vivo. Cell death was also promoted when Akt inhibition was combined with the vacuolar H+–adenosine triphosphatase inhibitor bafilomycin A1 or with cathepsin inhibition. These results suggest that blocking lysosomal degradation can be detrimental to cancer cell survival when autophagy is activated, providing rationale for a new therapeutic approach to enhancing the anticancer efficacy of PI3K–Akt pathway inhibition.
D. Gray's present address is Chemistry and Biology Graduate Program, University of California, San Francisco, San Francisco, CA 94158.
Abbreviations used in this paper: AO, acridine orange; AV, autophagic vacuole; AVO, acidic vesicular organelle; Ba, bafilomycin A1; CCD, charge-coupled device; CQ, chloroquine; Dox, doxycycline; IHC, immunohistochemistry; KD, knockdown; LAMP, lysosome-associated membrane protein; MDC, monodansylcadaverine; MEF, mouse embryonic fibroblast; mTOR, mammalian target of rapamycin; NAC, N-acetylcysteine; PARP, poly-ADP-ribose polymerase; PI, propidium iodide; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homologue; ROS, reactive oxygen species; shAkt, Akt-targeting shRNA; shRNA, short hairpin RNA.
© 2008 Degtyarev et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
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