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An Akt3 Splice Variant Lacking the Serine 472 Phosphorylation Site Promotes Apoptosis and Suppresses Mammary
Kimita Suyama1, Jiahong Yao1, Huizhi Liang1
1Department of Pathology and Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York.
Abstract:
The Akt pathway is a well-known promoter of tumor malignancy. Akt3 is expressed as two alternatively spliced variants, one of which lacks the key regulatory serine 472 phosphorylation site. Whereas the function of full-length Akt3 isoform (Akt3/+S472) is well-characterized, that of Akt3/-S472 isoform remains unknown. Despite being expressed at a substantially lower level than Akt3/+S472 in triple-negative breast cancer cells, specific ablation of Akt3/-S472 enhanced, whereas overexpression, suppressed mammary tumor growth, consistent with a significant association with patient survival duration relative to Akt3/+S472. These effects were due to striking induction of apoptosis, which was mediated by Bim upregulation, leading to conformational activation of Bax and caspase-3 processing. Bim accumulation was caused by marked endocytosis of EGF receptors with concomitant ERK attenuation, which stabilizes BIM. These findings demonstrate an unexpected function of an endogenously expressed Akt isoform in promoting, as opposed to suppressing, apoptosis, underscoring that Akt isoforms may exert dissonant functions in malignancy.Significance: These results illuminate an unexpected function for an endogenously expressed Akt isoform in promoting apoptosis, underscoring the likelihood that different Akt isoforms exert distinct functions in human cancer. Cancer Res; 78(1); 103-14. ©2017 AACR.
Insights
The Akt3/-S472 isoform unexpectedly promotes apoptosis in breast cancer, unlike its full-length counterpart. This finding reveals dissonant functions of Akt isoforms in cancer progression and patient survival.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Signaling
Background:
- The Akt pathway is implicated in promoting tumor malignancy.
- Akt3 has two alternatively spliced variants: Akt3/+S472 and Akt3/-S472.
- The function of Akt3/-S472 is largely unknown, contrasting with the well-characterized Akt3/+S472.
Purpose of the Study:
- To investigate the role of the Akt3/-S472 isoform in mammary tumor growth.
- To determine the functional impact of Akt3/-S472 on apoptosis and its association with patient survival.
- To elucidate the molecular mechanisms underlying the observed effects of Akt3/-S472.
Main Methods:
- Analysis of Akt3 isoform expression in triple-negative breast cancer cells.
- Experimental manipulation (ablation and overexpression) of Akt3/-S472.
- Assessment of mammary tumor growth, apoptosis induction, Bim upregulation, EGF receptor endocytosis, ERK signaling, and caspase-3 processing.
Main Results:
- Specific ablation of Akt3/-S472 enhanced mammary tumor growth, while overexpression suppressed it.
- Akt3/-S472 was associated with patient survival duration.
- The effects were mediated by Bim upregulation, leading to apoptosis through Bax activation and caspase-3 processing, driven by EGF receptor endocytosis and ERK attenuation.
Conclusions:
- Akt3/-S472 exhibits an unexpected pro-apoptotic function in breast cancer.
- Different Akt isoforms can exert dissonant functions in cancer malignancy.
- These findings highlight the complexity of Akt signaling in cancer and suggest potential therapeutic targets.