Resistance to the mTOR-inhibitor RAD001 elevates integrin α2- and β1-triggered motility, migration and invasion of prostate cancer cells

• Published in: British journal of cancer 2012-08, Vol.107 (5), p.847-855
• Main Authors: Tsaur, I, Makarević, J, Juengel, E, Gasser, M, Waaga-Gasser, A-M, Kurosch, M, Reiter, M, Wedel, S, Bartsch, G, Haferkamp, A, Wiesner, C, Blaheta, R A
• Format: Article
• Language: English
• Subjects: 631/67/1059/2326; 631/80/79/1236; 631/80/84; 692/699/67/589/466; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Adhesion - drug effects; Cell Adhesion - physiology; Cell Line, Tumor; Cell Movement - drug effects; Cell Movement - physiology; Drug Resistance; Epidemiology; Everolimus; Humans; Integrin alpha2 - biosynthesis; Integrin alpha2 - metabolism; Integrin beta1 - biosynthesis; Integrin beta1 - metabolism; Male; Medical sciences; Molecular Diagnostics; Molecular Medicine; Nephrology. Urinary tract diseases; Oncology; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Protein Kinase Inhibitors - pharmacology; Sirolimus - analogs & derivatives; Sirolimus - pharmacology; TOR Serine-Threonine Kinases - biosynthesis; TOR Serine-Threonine Kinases - metabolism; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2012.313

Background: Inhibitors of the mammalian target of rapamycin (mTOR) might become a novel tool to treat advanced prostate cancer. However, chronic drug exposure may trigger resistance, limiting the utility of mTOR inhibitors. Methods: Metastatic potential of PC3 prostate cancer cells, susceptible (PC3 par ) or resistant (PC3 res ) to the mTOR-inhibitor RAD001 was investigated. Adhesion to vascular endothelium or immobilised collagen, fibronectin and laminin was quantified. Motility, migration and invasion were explored by modified Boyden chamber assay. Integrin α and β subtypes were analysed by flow cytometry, western blotting and real-time PCR. Integrin-related signalling, EGFr, Akt, p70S6kinase and ERK1/2 activation were determined. Results: Adhesion was reduced, whereas motility, migration and invasion were enhanced in PC3 res . The α 2 and β 1 integrin subtypes were dramatically elevated, integrins α 1 and α 6 were lowered, whereas α 5 was nearly lost in PC3 res . Activation of the Akt signalling pathway was strongly upregulated in these cells. Treating PC3 par cells with RAD001 reduced motility, migration and invasion and deactivated Akt signalling. Blocking studies revealed that α 2 and β 1 integrins significantly trigger the motile behaviour of the tumour cells. Conclusion: Chronic RAD001 treatment caused resistance development characterised by distinct modification of the integrin-expression profile, driving prostate cancer cells towards high motility.