Abstract
Abstract The Met receptor tyrosine kinase (RTK) and its ligand, hepatocyte growth factor (HGF), are potent mediators of epithelial-mesenchymal transition and an invasive growth program. The HGF-Met signaling axis plays a significant role in the development or progression of many human cancers, and elevated Met expression is associated with poor prognosis and the basal subtype in breast cancer. Met signaling is regulated temporally and spatially through endocytic trafficking to degradative or recycling compartments, and delayed Met trafficking to the degradative pathway promotes enhanced cell migration, adhesion-independent growth and tumorigenesis. It is now recognized that autophagy, an intracellular degradative process, utilizes the endocytic system in both formation and maturation of double-membraned autophagosomes. Autophagy can have both tumor promoting and tumor suppressor roles in different contexts or stages of disease. We hypothesized that reprogramming of endocytic membrane system to support an autophagic starvation response may alter Met RTK trafficking, and therefore modulate tumorigenic signaling. To test this, we utilized MDA-MB-231 and BT-549 triple-negative breast cancer cell lines, as well as Hela cells, as models to study the trafficking and signaling of the Met RTK under conditions of autophagic stimulation or inhibition. Following HGF stimulation and receptor internalization, Met engages with core autophagic machinery in a starvation-dependent manner. Increased autophagosome formation decreases Met recycling to the plasma membrane, which can be rescued by shRNA-mediated knockdown of genes required for autophagy initiation. We demonstrate that the autophagic process negatively regulates signaling of Met through the PI3K/Akt and MAPK pathways and decreases Met-dependent cellular responses. These findings identify Met RTK regulation as a potential tumor-suppressive function of autophagy. Citation Format: Emily S. Bell, Dongmei Zuo, Morag Park. Autophagic regulation of the Met receptor tyrosine kinase in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3453. doi:10.1158/1538-7445.AM2014-3453
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