Akt inhibition promotes autophagy and sensitizes PTEN-null tumors to lysosomotropic agents.
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.
Genentech, Inc., South San Francisco, CA 94080, USA.
Michael
M
Degtyarev
Ann
A
De Mazière
Christine
C
Orr
Jie
J
Lin
Brian B
BB
Lee
Janet Y
JY
Tien
Wei W
WW
Prior
Suzanne
S
van Dijk
Hong
H
Wu
Daniel C
DC
Gray
David P
DP
Davis
Howard M
HM
Stern
Lesley J
LJ
Murray
Klaus P
KP
Hoeflich
Judith
J
Klumperman
Lori S
LS
Friedman
Kui
K
Lin
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D000071193:Autophagy-Related Protein 7; D001596:Benzylamines / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D005663:Furans / Q000494:pharmacology; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
C501521:Akt-I-1,2 compound; D001596:Benzylamines; D005663:Furans; D018942:Macrolides; C522973:PI103; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D011810:Quinoxalines; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D002738:Chloroquine; C040929:bafilomycin A1; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D006180:Proton-Translocating ATPases; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes