Abstract
BackgroundThe phosphatidylinositol 3-kinase–regulated protein kinase, Akt, plays an important role in the initiation and progression of human cancer. Mammalian cells express three Akt isoforms (Akt1–3), which are encoded by distinct genes. Despite sharing a high degree of amino acid identity, phenotypes observed in knockout mice suggest that Akt isoforms are not functionally redundant. The relative contributions of the different Akt isoforms to oncogenesis, and the effect of their deficiencies on tumor development, are not well understood.MethodsHere we demonstrate that Akt isoforms have non-overlapping and sometimes opposing functions in tumor initiation and progression using a viral oncogene-induced mouse model of lung cancer and Akt isoform-specific knockout mice.ResultsAkt1 ablation significantly delays initiation of lung tumor growth, whereas Akt2 deficiency dramatically accelerates tumorigenesis in this mouse model. Ablation of Akt3 had a small, not statistically significant, stimulatory effect on tumor induction and growth by the viral oncogene. Terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling and Ki67 immunostaining of lung tissue sections revealed that the delayed tumor induction in Akt1−/− mice was due to the inhibitory effects of Akt1 ablation on cell growth and survival. Conversely, the accelerated growth rate of lung tumors in Akt2−/− and Akt3−/− mice was due to increased cell proliferation and reduced tumor cell apoptosis. Investigation of Akt signaling in tumors from Akt knockout mice revealed that the lack of Akt1 interrupted the propagation of signaling in tumors to the critical downstream targets, GSK-3α/β and mTOR.ConclusionsThese results demonstrate that the degree of functional redundancy between Akt isoforms in the context of lung tumor initiation is minimal. Given that this mouse model exhibits considerable similarities to human lung cancer, these findings have important implications for the design and use of Akt inhibitors for the treatment of lung cancer.
Highlights
Lung cancer accounts for 27% of all cancer-related deaths each year making it the most common cause of cancer-related death in both males and females
We have developed a tractable mouse model to study lung cancer induced by the Jaagsiekte sheep retrovirus (JSRV) envelope protein (Jenv) that involves delivering the Jenv gene to the mouse respiratory tract using a replication defective adeno-associated virus (AAV) vector
All three Akt isoforms are expressed in the mouse lung To determine the relative expression level of Akt isoforms within mouse lungs, total cell lysates were prepared from the lung tissue of 8-week-old wild type (WT), Akt12/2, Akt22/2, and Akt32/2 C57BL/6 mice and probed with antibodies specific for Akt1, Akt2, Akt3, and pan-Akt
Summary
Lung cancer accounts for 27% of all cancer-related deaths each year making it the most common cause of cancer-related death in both males and females. The ability of JSRV to cause lung tumors in sheep that are histologically and phenotypically similar to those frequently found in humans, that of never smokers, make it an attractive model for understanding the etiology and carcinogenesis of human lung cancer [2,3,4]. Unlike most replication-competent retroviruses, which cause cancer by insertional activation of cellular oncogenes or by acquisition of cellular oncogenes, the envelope protein of JSRV is itself a potent oncogene that when expressed in mouse [5] or sheep lungs [6] is sufficient to induce lung cancer. We have developed a tractable mouse model to study lung cancer induced by the JSRV envelope protein (Jenv) that involves delivering the Jenv gene to the mouse respiratory tract using a replication defective adeno-associated virus (AAV) vector. The relative contributions of the different Akt isoforms to oncogenesis, and the effect of their deficiencies on tumor development, are not well understood
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