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Metformin suppresses HIF‐1α expression in cancer‐associated fibroblasts to prevent tumor‐stromal cross talk in breast cancer

Authors :
Qian Ning
Xin Jing
Wei Li
Gaili An
Lin Zhao
Xinhan Zhao
Jianjun Lei
Shan Shao
Lingxiao Zhang
Du Meng
Minna Luo
Source :
The FASEB Journal. 34:10860-10870
Publication Year :
2020
Publisher :
Wiley, 2020.

Abstract

The tumor microenvironment (TME) is a crucial factor in cancer progression. In breast cancer, cancer-associated fibroblasts (CAFs) and the derived stromal components have been recognized as comprising the majority of the pathological structure of the TME. In this study, we show that metformin (Met), a diabetes drug, transforms CAFs in the TME. Met disrupts tumor-stromal cross talk by preventing breast cancer cell transforming growth factor-β (TGF-β) signaling and the production of stromal-derived factor-1 (SDF-1) and interleukin-8 (IL-8) by CAFs. The suppression of bidirectional signaling between tumor cells and CAFs by Met is attributed to increased phospho-AMP kinase (p-AMPK) levels. By upregulating p-AMPK in CAFs, Met induces prolyl hydroxylases (PHDs), leading to the degradation of hypoxia-inducible factor-1α (HIF-1α) in CAFs. Moreover, interruption of HIF-1α-driven SDF-1 signaling in CAFs by Met leads to decreased breast cancer cell invasion. These findings suggest that Met may be used to target tumor-promoting signaling between CAFs and breast cancer cells in the TME.

Details

ISSN :
15306860 and 08926638
Volume :
34
Database :
OpenAIRE
Journal :
The FASEB Journal
Accession number :
edsair.doi.dedup.....087d33a2006e062d249b72817a62623a