The Fibronectin III‐1 Domain Activates a PI3‐Kinase/Akt Signaling Pathway Leading to αvβ5 Integrin Activation and TRAIL Resistance in Human Lung Cancer Cells
Abstract
Fibronectin is a mechanically sensitive protein which is organized in the extracellular matrix as a network of interacting fibrils. The lung tumor stroma is enriched for fibronectin which is thought to contribute to metastasis and drug resistance. Fibronectin is an elastic, multi‐modular protein made up of individually folded domains, some of which can stretch in response to increased mechanical tension. Very little is known about the relationship of fibronectin's unfolded domains to lung cancer resistance to chemotherapy. In the present study, we evaluated the impact of unfolding the first Type III domain of fibronectin (FnIII‐1c) on TRAIL resistance. FnIII‐1c inhibited TRAIL‐induced activation of caspase 8 and subsequent apoptosis in H460 lung cancer cells. FnIII‐1c treatment was associated with the activation of the PI3K/Akt pathway and the αvβ5 integrin receptor for vitronectin, both of which were required for TRAIL resistance. Immunohistochemical staining of sections from non‐small cell lung cancers showed that vitronectin was localized around blood vessels and in the tumor‐stroma interface. These findings suggest that unfolding of Type III domains within the fibronectin matrix may promote TRAIL resistance through the activation of a PI3K/Akt/αvβ5 signaling axis and point to a novel mechanism by which changes in secondary structure of fibronectin contribute to cancer cell resistance to apoptosis.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 01, 2016
- Source ID
- 10.1096/fasebj.30.1_supplement.lb82
Entities
People
- Christina Cho
- Paula Mckeown‐longo
Organizations
- Albany Medical College
- National Institutes of Health
- United States Department of Defense