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.
Similar content being viewed by others
Reference
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.
DeSantis CE, Lin CC, Mariotto AB, Siegel RL, Stein KD, Kramer JL, Alteri R, et al. Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin. 2014;64:252–71.
Remon J, Lianes P, Martínez S, Velasco M, Querol R, Zanui M. Adjuvant treatment in resected non-small cell lung cancer: current and future issues. Crit Rev Oncol Hematol. 2013;88:375–86.
Rossi A, Chiodini P, Sun JM, O’Brien ME, von Plessen C, Barata F, Park K, et al. Six versus fewer planned cycles of first-line platinum-based chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual patient data. Lancet Oncol. 2014;15:1254–62.
Horn L, Visbal A, Leighl NB. Docetaxel in non-small cell lung cancer impact on quality of life and pharmacoeconomics. Drugs Aging. 2007;24:411–28.
Davies AM, Lara Jr PN, Mack PC, Gandara DR. Docetaxel in non-small cell lung cancer: a review. Expert Opin Pharmacother. 2003;4:553–65.
Yang L, Zhou Y, Li Y, Zhou J, Wu Y, Cui Y, Yang G, et al. Mutations of p53 and KRAS activate NF-κB to promote chemoresistance and tumorigenesis via dysregulation of cell cycle and suppression of apoptosis in lung cancer cells. Cancer Lett. 2015;357:520–6.
Engels FK, Sparreboom A, Mathot RA, Verweij J. Potential for improvement of docetaxel-based chemotherapy: a pharmacological review. Br J Cancer. 2005;93:173–7.
Tamaki H, Harashima N, Hiraki M, Arichi N, Nishimura N, Shiina H, Naora K, et al. Bcl-2 family inhibition sensitizes human prostate cancer cells to docetaxel and promotes unexpected apoptosis under caspase-9 inhibition. Oncotarget. 2014;5:11399–412.
Kaspar M, Zardi L, Neri D. Fibronectin as target for tumor therapy. Int J Cancer. 2006;118:1331–9.
Xing H, Weng D, Chen G, Tao W, Zhu T, Yang X, Meng L, et al. Activation of fibronectin/PI-3 K/Akt2 leads to chemoresistance to docetaxel by regulating survivin protein expression in ovarian and breast cancer cells. Cancer Lett. 2008;261:108–19.
Pan CW, Shen ZJ, TT W, Tang XY, Wang M, Sun J, et al. Cell adhesion to fibronectin induces mitomycin C resistance in bladder cancer cells. BJU Int. 2009;104:1774–9.
Qin S, Xu C, Li S, Wang X, Sun X, Wang P, Zhang B, et al. Hyperthermia induces apoptosis by targeting survivin in esophageal cancer. Oncol Rep. 2015;34:2656–64.
Dumontet C, Sikic BI. Mechanisms of action of and resistance to antitubulin agents: microtubule dynamics, drug transport and cell death. J Clin Oncol. 1999;17:1061–70.
Fojo T, Menefee M. Mechanisms of multidrug resistance: the potential role of microtubule-stabilizing agents. Ann Oncol. 2007;18(Suppl 5):v3–8.
Kavallaris M. Microtubules and resistance to tubulin-binding agents. Nat Rev Cancer. 2010;10:194–204.
Ahmed N, Riley C, Rice G, Quinn M. Role of integrin receptors for fibronectin, collagen and laminin in the regulation of ovarian carcinoma functions in response to a matrix microenvironment. Clin Exp Metastasis. 2005;22:391–402.
Hazlehurst LA, Landowski TH, Dalton WS. Role of the tumor microenvironment in mediating de novo resistance to drugs and physiological mediators of cell death. Oncogene. 2003;22:7396–402.
Nakagawa Y, Nakayama H, Nagata M, Yoshida R, Kawahara K, Hirosue A, Tanaka T, et al. Overexpression of fibronectin confers cell adhesion-mediated drug resistance (CAM-DR) against 5-FU in oral squamous cell carcinoma cells. Int J Oncol. 2014;44:1376–84.
Sethi T, Rintoul RC, Moore SM, MacKinnon AC, Salter D, Choo C, Chilvers ER, et al. Extracellular matrix proteins protect small cell lung cancer cells against apoptosis: a mechanism for small cell lung cancer growth and drug resistance in vivo. Nat Med. 1999;5:662–8.
Xing H, Cao Y, Weng D, Tao W, Song X, Wang W, Meng L, et al. Fibronectin-mediated activation of Akt2 protects human ovarian and breast cancer cells from docetaxel-induced apoptosis via inhibition of the p38 pathway. Apoptosis. 2008;13:213–23.
Fornaro M, Plescia J, Chheang S, Tallini G, Zhu YM, King M, Altieri DC, et al. Fibronectin protects prostate cancer cells from tumor necrosis factor-alpha-induced apoptosis via the AKT/survivin pathway. J Biol Chem. 2003;278:50402–11.
Qiu Z, Kwon AH, Tsuji K, Kamiyama Y, Okumura T, Hirao Y. Fibronectin prevents D-galactosamine/lipopolysaccharide-induced lethal hepatic failure in mice. Shock. 2006;25:80–7.
Kwon AH, Qiu Z, Tsuji K, Miyaso T, Okumura T. Fibronectin prevents endotoxin shock after partial hepatectomy in rats via inhibition of nuclear factor-kappaB and apoptosis. Exp Biol Med (Maywood). 2007;232:895–903.
Meng XN, Jin Y, Yu Y, Bai J, Liu GY, Zhu J, Zhao YZ, et al. Characterisation of fibronectin-mediated FAK signalling pathways in lung cancer cell migration and invasion. Br J Cancer. 2009;101:327–34.
Yu L, Thakur S, Leong-Quong RY, Suzuki K, Pang A, Bjorge JD, Riabowol K, et al. Src regulates the activity of the ING1 tumor suppressor. PLoS One. 2013;8:e60943.
Hiscox S, Jordan NJ, Morgan L, Green TP, Nicholson RI. Src kinase promotes adhesion-independent activation of FAK and enhances cellular migration in tamoxifen-resistant breast cancer cells. Clin Exp Metastasis. 2007;24:157–67.
Creedon H, Brunton VG. Src kinase inhibitors: promising cancer therapeutics? Crit Rev Oncog. 2012;17:145–59.
Cursi S, Rufini A, Stagni V, Condò I, Matafora V, Bachi A, Bonifazi AP, et al. Src kinase phosphorylates caspase-8 on Tyr380: a novel mechanism of apoptosis suppression. EMBO J. 2006;25:1895–905.
Zhao Y, Sui X, Ren H. From procaspase-8 to caspase-8: revisiting structural functions of caspase-8. J Cell Physiol. 2010;225:316–20.
Finlay D, Vuori K. Novel noncatalytic role for caspase-8 in promoting Src-mediated adhesion and Erk signaling in neuroblastoma cells. Cancer Res. 2007;67:11704–11.
Acknowledgments
We would like to thank Edanz English Editing for editing the English language in the manuscript.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
All the clinical studies and animal studies were conducted in accordance with the protocol approved by the Ethics Committee of the First Affiliated Hospital of Xi’an Jiaotong University.
Funding
This study was supported by the National Natural Science Foundation of China (81402506).
Conflicts of interest
None
Additional information
Sida Qin and Boxiang Zhang contributed equally to this work.
Rights and permissions
About this article
Cite this article
Qin, S., Zhang, B., Xiao, G. et al. Fibronectin protects lung cancer cells against docetaxel-induced apoptosis by promoting Src and caspase-8 phosphorylation. Tumor Biol. 37, 13509–13520 (2016). https://doi.org/10.1007/s13277-016-5206-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13277-016-5206-8