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

BackgroundFibronectin 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 TNF-related apoptosis inducing ligand (TRAIL) resistance.MethodsNCI-H460 non-small cell lung cancer cells were treated with FnIII-1c then assessed for TRAIL-induced apoptosis. Subsequent analysis of FnIII-1c-mediated signaling pathways was also completed. Human non-small cell lung cancer tissue sections were assessed for the expression of vitronectin by immunohistochemistry.ResultsFnIII-1c inhibited TRAIL-induced activation of caspase 8 and subsequent apoptosis in NCI-H460 lung cancer cells. FnIII-1c treatment was associated with the activation of the phosphatidylinositol-3-kinase/alpha serine/threonine kinase (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.ConclusionsUnfolding 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.

Ovarian cancer‐associated mesothelial cells induce acquired platinum‐resistance in peritoneal metastasis via the FN1/Akt signaling pathway

“…Moreover, FN1 has been described as having a pivotal role in the progression of OvCa cells, and is also reported to induce resistance for specific chemotherapeutic agents . Although few reports have described a direct association between platinum‐resistance and FN1 expression in stromal cells of peritoneal metastasis, signal transduction from FN1 to Akt via integrin and PI3K has been recognized as a critical pathway in cancer progression . Adding to this body of research, we demonstrated that activation of the Akt signaling pathway, induced by FN1 interactions, was associated with platinum‐resistance in OvCa cells in direct contact with OCAMs.…”

“…52,53 Although few reports have described a direct association between platinum-resistance and FN1 expression in stromal cells of peritoneal metastasis, signal transduction from FN1 to Akt via integrin and PI3K has been recognized as a critical pathway in cancer progression. 54,55 Adding to this body of research, we demonstrated that activation of the Akt signaling pathway, induced by FN1 interactions, was associated with platinum-resistance in OvCa cells in direct contact with OCAMs. Thus, if we can inhibit mesothelial conversion to OCAMs or inhibit the FN1/Akt signaling pathway axis, we may be able to effectively control the development of peritoneal metastatic tumors even with the use of conventional platinum-based chemotherapy.…”

Fibronectin Promotes the Malignancy of Glioma Stem-Like Cells Via Modulation of Cell Adhesion, Differentiation, Proliferation and Chemoresistance

“…Given that FN has been shown to induce cell adhesion–mediated drug resistance in various tumor cells (Pontiggia et al, 2012 ; Cho et al, 2016 ), we were interested in whether it had a similar capability in GSCs. The traditional chemotherapeutic reagent, temozolomide, shows very low cytotoxicity for GSCs (Yu et al, 2017 ).…”

Tumor necrosis factor‑related apoptosis‑inducing ligand additive with Iodine‑131 of inhibits non‑small cell lung cancer cells through promoting apoptosis

“…Furthermore, combination of TRAIL and actinomycin D liposomes has been identified to significantly promote anti-tumor effects in NSCLC cells ( 16 ). Additionally, TRAIL downregulates fibronectin (FN), Vimentin (VN) and E-cadherin (EN) expression, which further leads to growth inhibition of tumor cells ( 17 ). These studies suggest that TRAIL may be a potential anti-cancer agent for the treatment of human NSCLC.…”