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

Christopher M. Dower, Neema Bhat, Edward W. Wang, Hong-Gang Wang

Research output: Contribution to journalArticle

6 Citations (Scopus)

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 autophagy promotes metastasis via induction of the fibronectin integrin signaling axis. Indeed, loss of ULK1 function increased fibronectin deposition in the hypoxic TME. Together, our results indicated that hypoxia-regulated autophagy suppresses metastasis in breast cancer by preventing tumor fibrosis. These results also suggest cautions in the development of autophagy-based strategies for cancer treatment. Cancer Res; 77(3); 646-57. Ó2016 AACR.

Original languageEnglish (US)
Pages (from-to)646-657
Number of pages12
JournalCancer Research
Volume77
Issue number3
DOIs
StatePublished - Feb 1 2017

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Autophagy
Breast Neoplasms
Neoplasm Metastasis
Lung
Tumor Microenvironment
Fibronectins
Neoplasms
Phosphotransferases
Gene Expression Profiling
Heterografts
Integrins
Proteomics
Small Interfering RNA
Cell Movement
Fibrosis
Food
Hypoxia

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Dower, Christopher M. ; Bhat, Neema ; Wang, Edward W. ; Wang, Hong-Gang. / Selective Reversible Inhibition of Autophagy in Hypoxic Breast Cancer Cells Promotes Pulmonary Metastasis. In: Cancer Research. 2017 ; Vol. 77, No. 3. pp. 646-657.
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Selective Reversible Inhibition of Autophagy in Hypoxic Breast Cancer Cells Promotes Pulmonary Metastasis. / Dower, Christopher M.; Bhat, Neema; Wang, Edward W.; Wang, Hong-Gang.

In: Cancer Research, Vol. 77, No. 3, 01.02.2017, p. 646-657.

Research output: Contribution to journalArticle

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