Fibronectin confers survival against chemotherapeutic agents but not against radiotherapy in DU145 prostate cancer cells: involvement of the insulin like growth factor-1 receptor.
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.
Thomas
Francis
F
Department of Clinical Sciences North Bristol, Southmead Hospital, Bristol, UK. francisthomask@hotmail.com
Holly
Jeff M P
JM
Persad
Raj
R
Bahl
Amit
A
Perks
Claire M
CM
D000704:Analysis of Variance; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D015153:Blotting, Western; D002452:Cell Count; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects* / Q000528:radiation effects; D002478:Cells, Cultured; D002518:Ceramides / Q000494:pharmacology; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D008297:Male; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D043823:Taxoids / Q000494:pharmacology; D019096:Vitronectin / Q000378:metabolism
D000970:Antineoplastic Agents; D002518:Ceramides; D005353:Fibronectins; D016023:Integrins; D007797:Laminin; D011838:Radiation-Sensitizing Agents; D043823:Taxoids; D019096:Vitronectin; D000077143:Docetaxel; D017526:Receptor, IGF Type 1; D054638:Dual Specificity Phosphatase 1