Selective Reversible Inhibition of Autophagy in Hypoxic Breast Cancer Cells Promotes Pulmonary Metastasis.

ABSTRACT: Autophagy influences how cancer cells respond to nutrient deprivation and hypoxic stress, two hallmarks of the tumor microenvironment (TME). In this study, we explored the impact of autophagy on the pathophysiology of breast cancer cells using a novel hypoxia-dependent, reversible dominant-negative strategy to regulate autophagy at the cellular level within the TME. Suppression of autophagy via hypoxia-induced expression of the kinase-dead unc-51-like autophagy-activating kinase (ULK1) mutant K46N increased lung metastases in MDA-MB-231 xenograft mouse models. Consistent with this effect, expressing a dominant-negative mutant of ULK1 or ATG4b or a ULK1-targeting shRNA facilitated cell migration in vitro Functional proteomic and transcriptome analysis revealed that loss of hypoxia-regulated

SUBMITTER: Dower CM 

PROVIDER: S-EPMC5300746 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature