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1.
Mol Neurobiol ; 53(9): 5985-5994, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-26526841

RESUMO

Maintenance of intracellular proteostasis is essential for neuronal function, and emerging data support the view that disturbed proteostasis plays an important role in brain aging and the pathogenesis of age-related neurodegenerative disorders such as Alzheimer's disease (AD). sAPPalpha (sAPPα), the extracellularly secreted N-terminal alpha secretase cleavage product of the amyloid precursor protein (APP), has an established function in neuroprotection. Recently, we provided evidence that membrane-bound holo-APP functionally cooperates with sAPPα to mediate neuroprotection via activation of the Akt survival signaling pathway and sAPPα directly affects proteostasis. Here, we demonstrate that in addition to its anti-apoptotic function, sAPPα has effects on neuronal proteostasis under conditions of proteasomal stress. In particular, recombinant sAPPα significantly suppressed MG132-triggered expression of the co-chaperone BAG3 and aggresome formation, and it partially rescued proteasomal activity in a dose-dependent manner in SH-SY5Y neuroblastoma cells. In analogy, sAPPα was able to inhibit MG132-induced BAG3 expression in primary hippocampal neurons. Strikingly, these sAPPα-induced changes were unaltered in APP-depleted SH-SY5Y cells and APP-deficient neurons, demonstrating that holo-APP is not required for this particular function of sAPPα. Importantly, recombinant sAPPbeta (sAPPß) failed to modulate BAG3 expression and proteostasis in APP-proficient wild-type (wt) cells, indicating that these biological effects are highly selective for sAPPα. In conclusion, we demonstrate that modulation of proteostasis is a distinct biological function of sAPPα and does not require surface-bound holo-APP. Our data shed new light on the physiological functions of APP and the interplay between APP processing and proteostasis during brain aging.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Membrana Celular/metabolismo , Fragmentos de Peptídeos/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Animais , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Humanos , Leupeptinas/farmacologia , Camundongos Endogâmicos C57BL , Proteínas Recombinantes/farmacologia
2.
Neoplasia ; 17(7): 564-73, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26297434

RESUMO

The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) is overactivated in malignant glioma and plays a key role in promoting cell survival, thereby increasing the acquired apoptosis resistance of these tumors. Here we investigated the STAT3/myeloid cell leukemia 1 (MCL1) signaling pathway as a target to overcome the resistance of glioma cells to the Bcl-2-inhibiting synthetic BH3 mimetic ABT-737. Stable lentiviral knockdown of MCL1 sensitized LN229 and U87 glioma cells to apoptotic cell death induced by single-agent treatment with ABT-737 which was associated with an early activation of DEVDase activity, cytochrome c release, and nuclear apoptosis. Similar sensitizing effects were observed when ABT-737 treatment was combined with the multikinase inhibitor sorafenib which effectively suppressed levels of phosphorylated STAT3 and MCL1 in MCL1-proficient LN229 and U87 glioma cells. In analogous fashion, these synergistic effects were observed when we combined ABT-737 with the STAT3 inhibitor WP-1066. Lentiviral knockdown of the activating transcription factor 5 combined with subsequent quantitative polymerase chain reaction analysis revealed that sorafenib-dependent suppression of MCL1 occurred at the transcriptional level but did not depend on activating transcription factor 5 which previously had been proposed to be essential for MCL1-dependent glioma cell survival. In contrast, the constitutively active STAT3 mutant STAT3-C was able to significantly enhance MCL1 levels under sorafenib treatment to retain cell survival. Collectively, these data demonstrate that sorafenib targets MCL1 in a STAT3-dependent manner, thereby sensitizing glioma cells to treatment with ABT-737. They also suggest that targeting STAT3 in combination with inducers of the intrinsic pathway of apoptosis may be a promising novel strategy for the treatment of malignant glioma.


Assuntos
Compostos de Bifenilo/farmacologia , Glioma/patologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Niacinamida/análogos & derivados , Nitrofenóis/farmacologia , Compostos de Fenilureia/farmacologia , Fator de Transcrição STAT3/metabolismo , Sulfonamidas/farmacologia , Fatores Ativadores da Transcrição/genética , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/genética , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Citocromos c/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Niacinamida/farmacologia , Peptídeo Hidrolases/metabolismo , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Piridinas/farmacologia , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Sorafenibe , Tirfostinas/farmacologia
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