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Inhibition of the Insulin-Like Growth Factor-1 Receptor Enhances Effects of Simvastatin on Prostate Cancer Cells in Co-Culture with Bone
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Medicine, Department of Odontology, School of Dentistry.
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2013 (English)In: Cancer microenvironment : official journal of the International Cancer Microenvironment Society, ISSN 1875-2292, Vol. 6, no 3, 231-240 p.Article in journal (Refereed) Published
Abstract [en]

Prostate cancer (PC) bone metastases show weak responses to conventional therapies. Bone matrix is rich in growth factors, with insulin-like growth factor-1 (IGF-1) being one of the most abundant. IGF-1 acts as a survival factor for tumor cells and we speculate that bone-derived IGF-1 counteracts effects of therapies aimed to target bone metastases and, consequently, that therapeutic effects could be enhanced if given in combination with IGF-1 receptor (IGF-1R) inhibitors. Simvastatin inhibits the mevalonate pathway and has been found to induce apoptosis of PC cells. The aims of this study were to confirm stimulating effects of bone-derived IGF-1 on PC cells and to test if IGF-1R inhibition enhances growth inhibitory effects of simvastatin on PC cells in a bone microenvironment. The PC-3 and 22Rv1 tumor cell lines showed significantly induced cell growth when co-cultured with neonatal mouse calvarial bones. The tumor cell IGF-1R was activated by calvariae-conditioned media and neutralization of bone-derived IGF-1 abolished the calvarium-induced PC-3 cell growth. Treatment of PC-3 and 22Rv1 cells with simvastatin, or the IGF-1R inhibitor NVP-AEW541, reduced tumor cell numbers and viability, and induced apoptosis. Combined simvastatin and NVP-AEW541 treatment resulted in enhanced growth inhibitory effects compared to either drug given alone. Effects of simvastatin involved down-regulation of IGF-1R in PC-3 and of constitutively active androgen receptor variants in 22Rv1 cells. In conclusion, we suggest that IGF-1 inhibition may be a way to strengthen effects of apoptosis-inducing therapies on PC bone metastases; a possibility that needs to be further tested in pre-clinical models.

Place, publisher, year, edition, pages
Springer, 2013. Vol. 6, no 3, 231-240 p.
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Cancer and Oncology
URN: urn:nbn:se:umu:diva-65834DOI: 10.1007/s12307-013-0129-zPubMedID: 23335094OAI: diva2:604937
Available from: 2013-02-12 Created: 2013-02-12 Last updated: 2014-02-07Bibliographically approved

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Nordstrand, AnnikaLundholm, MarieLarsson, AndreasLerner, Ulf HWidmark, AndersWikström, Pernilla
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