| Abstrakt: |
Simple Summary: Insulin-like growth factor-1 (IGF-1) is a growth hormone and is implicated in prostate cancer progression. Most prostate cancers begin in an androgen-dependent state so that androgen deprivation therapy results in improved clinical outcome. However, some cancerous cells may survive androgen deprivation, growing into therapy-resistant, androgen-independent prostate cancer. The present study investigated the influence of IGF-1 on tumor growth and migration properties using androgen-dependent LNCaP and VCaP and androgen-independent PC3 and DU145 prostate cancer cells. Stimulation with IGF-1 activated growth in all cell lines. There were changes in transmembrane receptors (integrins) that bind cells to each other and changes in focal adhesion kinase that controls cell motility. Intracellular Akt/mTOR signaling, regulating cell division, was also activated. Thus, it seems that prostate cancer progression is controlled by a fine-tuned network between IGF-1-driven integrin-FAK signaling and the Akt-mTOR pathway. Concerted targeting of both pathways may, therefore, help prevent cancer dissemination. Insulin-like growth factor-1 (IGF-1)-related signaling is associated with prostate cancer progression. Links were explored between IGF-1 and expression of integrin adhesion receptors to evaluate relevance for growth and migration. Androgen-resistant PC3 and DU145 and androgen-sensitive LNCaP and VCaP prostate cancer cells were stimulated with IGF-1 and tumor growth (all cell lines), adhesion and chemotaxis (PC3, DU145) were determined. Evaluation of Akt/mTOR-related proteins, focal adhesion kinase (FAK) and integrin α and β subtype expression followed. Akt knock-down was used to investigate its influence on integrin expression, while FAK blockade served to evaluate its influence on mTOR signaling. Integrin knock-down served to investigate its influence on tumor growth and chemotaxis. Stimulation with IGF-1 activated growth in PC3, DU145, and VCaP cells, and altered adhesion and chemotactic properties of DU145 and PC3 cells. This was associated with time-dependent alterations of the integrins α3, α5, αV, and β1, FAK phosphorylation and Akt/mTOR signaling. Integrin blockade or integrin knock-down in DU145 and PC3 cells altered tumor growth, adhesion, and chemotaxis. Akt knock-down (DU145 cells) cancelled the effect of IGF-1 on α3, α5, and αV integrins, whereas FAK blockade cancelled the effect of IGF-1 on mTOR signaling (DU145 cells). Prostate cancer growth and invasion are thus controlled by a fine-tuned network between IGF-1 driven integrin-FAK signaling and the Akt-mTOR pathway. Concerted targeting of integrin subtypes along with Akt-mTOR signaling could, therefore, open options to prevent progressive dissemination of prostate cancer. [ABSTRACT FROM AUTHOR] |
