title: Fibronectin protects lung cancer cells against docetaxel-induced apoptosis by promoting Src and caspase-8 phosphorylation.
abstract: Fibronectin is involved in orchestrating many diverse cellular behaviors, including adhesion, invasion, differentiation, and proliferation and recently has also been shown to participate in the development of chemoresistance. In this study, we found that fibronectin expression was inversely correlated with clinical responses to docetaxel treatment in non-small cell lung cancer patients. Subsequently, we showed that fibronectin pretreatment could enhance cell viability and reduce apoptosis in docetaxel-treated lung cancer cells because fibronectin induced phosphorylated Src and caspase-8, rendering the later inactive, thus inhibiting docetaxel-induced apoptosis. The inhibition of apoptosis by fibronectin was found to be enhanced by Src overexpression and reversed by Src knockdown in lung cancer cells. Further investigation revealed that a downregulation of phospho-Src via treatment with a Src kinase inhibitor could also abolish fibronectin activity and recover docetaxel-induced apoptosis. Molecular studies revealed that this reversion was due to decreased phospho-Src levels rather than a reduction in total Src expression. Inhibition of phospho-Src reduced phospho-caspase-8 and promoted caspase-8 activity, restoring apoptosis following docetaxel and fibronectin co-treatment. Finally, xenografts experiments demonstrated that fibronectin promoted lung cancer cell proliferation during docetaxel treatment in vivo. Our findings indicate that fibronectin promotes Src and caspase-8 phosphorylation in lung cancer cells, which decreases caspase-8 activation and protects tumor cells from docetaxel-induced apoptosis. Therefore, the fibronectin/Src/caspase-8 pathway may play a crucial role in docetaxel resistance in lung cancer.
authors.affiliation: Department Two of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China.
authors.forename: Sida
authors.initials: S
authors.lastname: Qin
authors.affiliation: Department Two of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China.
authors.forename: Boxiang
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department Two of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China.
authors.forename: Guodong
authors.initials: G
authors.lastname: Xiao
authors.affiliation: Department Two of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department Two of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: Department Two of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China.
authors.forename: Guanghong
authors.initials: G
authors.lastname: Huang
authors.affiliation: Department Two of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department Two of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.affiliation: Department Two of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China.
authors.forename: Huangzhen
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China. hellen.young87@gmail.com.
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department Two of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China. renhong@xjtu.edu.cn.
authors.forename: Hong
authors.initials: H
authors.lastname: Ren
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D053181:Caspase 8 / Q000378:metabolism*; D049109:Cell Proliferation; D000077143:Docetaxel; D005260:Female; D005353:Fibronectins / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010766:Phosphorylation; D011379:Prognosis; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D043823:Taxoids / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C067625:FN1 protein, human; D005353:Fibronectins; D043823:Taxoids; D000077143:Docetaxel; D016392:Proto-Oncogene Proteins pp60(c-src); D053181:Caspase 8
keywords: Apoptosis; Docetaxel; Fibronectin; Lung cancer