Fibronectin confers survival against chemotherapeutic agents but not against radiotherapy in DU145 prostate cancer cells: involvement of the insulin like growth factor-1 receptor

F Thomas, JMP Holly, Rajendra A Persad, Amit Bahl, Claire M Perks

Research output: Contribution to journalArticle (Academic Journal)peer-review

34 Citations (Scopus)

Abstract

BACKGROUND: Tumor growth is influenced by an increase in cell proliferation and a reduction in apoptosis; both of which are affected by alterations in extracellular matrix (ECM). Our aim was to assess if the susceptibility of prostate cancer cells to apoptosis induced by either chemotherapeutics or radiotherapy was altered by changes in the ECM. METHODS: Prostate cancer cell lines LNCaP and DU145 (androgen independent) cells were treated with chemotherapeutics (ceramide and docetaxel) or radiotherapy in the presence or absence of fibronectin, laminin, or vitronectin. Cell death was assessed using Trypan blue cell counting and apoptosis was confirmed by measuring PARP cleavage by Western immunoblotting (WIB). To identify a mechanism of action, changes in the abundance (WIB) or association (immunoprecipitation followed by WIB) of key proteins was also assessed. RESULTS: We found that fibronectin, but not laminin or vitronectin activated a survival pathway that protected DU145 but not LNCaP prostate cancer cells against ceramide and docetaxel-induced apoptosis but not that induced by radiotherapy. This survival effect involved the insulin-like growth factor (IGF-I) and beta1 integrin receptors and was associated with an increase in the recruitment of the beta1 integrin to a complex containing the IGF-IR and protein receptor for activated C kinase (RACK-1) and an increase in the abundance of a MAPK-phosphatase-1 (MKP-1). CONCLUSIONS: Changes in the ECM associated with disease progression may contribute to resistance to chemotherapeutic drugs but not to radiation therapy. The susceptibility to chemotherapy may be improved by targeting either the IGF-I or beta1 integrin receptors.
Translated title of the contributionFibronectin confers survival against chemotherapeutic agents but not against radiotherapy in DU145 prostate cancer cells: involvement of the insulin like growth factor-1 receptor
Original languageEnglish
Pages (from-to)856 - 865
Number of pages10
JournalProstate
Volume1;70(8)
DOIs
Publication statusPublished - Jun 2010

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