Akt inhibition promotes autophagy and sensitizes PTEN-null tumors to lysosomotropic agents

Journal of Cell Biology - Tập 183 Số 1 - Trang 101-116 - 2008
Michael Degtyarev1, Ann De Mazière2, Christine Orr1, Jie Lin1, Brian B. Lee1, Janet Tien1, Wei Wei Prior1, Suzanne van Dijk2, Hong Wu3, Daniel C. Gray1, David P. Davis1, Howard M. Stern1, Lesley Murray1, Klaus P. Hoeflich1, Judith Klumperman2, Lori S. Friedman1, Kwang‐Huei Lin1
1Genentech Inc.,** South San Francisco, CA 94080
22Cell Microscopy Center, Department of Cell Biology and Institute for Biomembranes, University Medical Center Utrecht, 3584 CX Utrecht, Netherlands
33Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095

Tóm tắt

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.

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Thông tin
Thông tin xuất bản

Journal of Cell Biology

Tập 183 Số 1

101-116

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