Regulation of autophagy through multiple independent hypoxic signaling pathways.
Curr Mol Med
; 9(4): 417-24, 2009 May.
Article
em En
| MEDLINE
| ID: mdl-19519399
ABSTRACT
The poorly developed vasculature in solid human tumors is responsible for a profound level of intra- and inter-tumor heterogeneity in oxygen concentration. High levels of hypoxia are associated with poor patient prognosis due in part to hypoxia-induced changes in cell metabolism, angiogenesis, invasiveness and resistance to therapy. Over the past decade several distinct oxygen sensing pathways that regulate the cellular response to hypoxia have been defined. These include transcriptional and translational responses initiated by oxygen-dependent stabilization of the HIF-1 transcription factor, activation of the unfolded protein response (UPR) and inhibition of the mTOR (mammalian target of rapamycin) kinase signaling pathway. Variations in the duration and severity of hypoxic stress differentially activate these responses and lead to substantial phenotypic variation amongst otherwise identical tumor cells. Nevertheless, several studies have provided links between HIF-, UPR- and mTOR-mediated signaling and the induction of autophagy. This process facilitates survival during metabolic stress and may also be an important mechanism for the removal of potentially toxic damaged proteins and organelles. We propose that overlapping mechanisms of autophagy regulation by HIF, mTOR and the UPR function to coordinately promote hypoxia tolerance and tumor cell survival.
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Bases de dados:
MEDLINE
Assunto principal:
Autofagia
/
Transdução de Sinais
/
Neoplasias
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Curr Mol Med
Assunto da revista:
BIOLOGIA MOLECULAR
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
Canadá