BACKGROUND: Proteolytically active prostate-specific antigen (PSA or kallikrein-related peptidase 3, KLK3) has been shown to exert antiangiogenic properties. High levels of PSA in prostatic tumors may thus slow down cancer progression by inhibiting angiogenesis. We hypothesize that factors stimulating the activity of PSA could be used to reduce prostate tumor growth. Using phage display, we have developed peptides C4 and B2 that stimulate the enzymatic activity of PSA. Our aim was to study whether these peptides enhance the antiangiogenic activity of PSA. METHODS: We used an in vitro angiogenesis assay where human umbilical vein endothelial cells (HUVECs) form tubular networks when they are grown on Matrigel. Proteolytically active PSA and peptides that stimulate the activity of PSA were added to the cells. Endothelial cell tube formation was quantified and expressed as an angiogenesis index. RESULTS: PSA reduced the angiogenesis index to ∼50% of controls both in serum-containing and serum-free medium. The addition of peptide C4 or B2 together with PSA caused a significant further decrease in angiogenesis index to ∼70% of that caused by PSA alone. A similar decrease in angiogenesis index was observed when PSA concentration was increased 2.4-fold of that used with peptides. CONCLUSIONS: The inhibitory effect of PSA on tube formation can be enhanced by the addition of peptides that stimulate the activity of PSA. This supports our hypothesis that stimulation of PSA activity can be used to reduce angiogenesis and thereby inhibit prostate tumor growth.
BACKGROUND: Proteolytically active prostate-specific antigen (PSA or kallikrein-related peptidase 3, KLK3) has been shown to exert antiangiogenic properties. High levels of PSA in prostatic tumors may thus slow down cancer progression by inhibiting angiogenesis. We hypothesize that factors stimulating the activity of PSA could be used to reduce prostate tumor growth. Using phage display, we have developed peptides C4 and B2 that stimulate the enzymatic activity of PSA. Our aim was to study whether these peptides enhance the antiangiogenic activity of PSA. METHODS: We used an in vitro angiogenesis assay where human umbilical vein endothelial cells (HUVECs) form tubular networks when they are grown on Matrigel. Proteolytically active PSA and peptides that stimulate the activity of PSA were added to the cells. Endothelial cell tube formation was quantified and expressed as an angiogenesis index. RESULTS:PSA reduced the angiogenesis index to ∼50% of controls both in serum-containing and serum-free medium. The addition of peptide C4 or B2 together with PSA caused a significant further decrease in angiogenesis index to ∼70% of that caused by PSA alone. A similar decrease in angiogenesis index was observed when PSA concentration was increased 2.4-fold of that used with peptides. CONCLUSIONS: The inhibitory effect of PSA on tube formation can be enhanced by the addition of peptides that stimulate the activity of PSA. This supports our hypothesis that stimulation of PSA activity can be used to reduce angiogenesis and thereby inhibit prostate tumor growth.
Authors: Kristian Meinander; Miikka Pakkala; Janne Weisell; Ulf-Håkan Stenman; Hannu Koistinen; Ale Närvänen; Erik A A Wallén Journal: ACS Med Chem Lett Date: 2013-12-16 Impact factor: 4.345
Authors: Shane Stegeman; Ernest Amankwah; Kerenaftali Klein; Tracy A O'Mara; Donghwa Kim; Hui-Yi Lin; Jennifer Permuth-Wey; Thomas A Sellers; Srilakshmi Srinivasan; Rosalind Eeles; Doug Easton; Zsofia Kote-Jarai; Ali Amin Al Olama; Sara Benlloch; Kenneth Muir; Graham G Giles; Fredrik Wiklund; Henrik Gronberg; Christopher A Haiman; Johanna Schleutker; Børge G Nordestgaard; Ruth C Travis; David Neal; Paul Pharoah; Kay-Tee Khaw; Janet L Stanford; William J Blot; Stephen Thibodeau; Christiane Maier; Adam S Kibel; Cezary Cybulski; Lisa Cannon-Albright; Hermann Brenner; Radka Kaneva; Manuel R Teixeira; Amanda B Spurdle; Judith A Clements; Jong Y Park; Jyotsna Batra Journal: Cancer Discov Date: 2015-02-17 Impact factor: 39.397
Authors: Johanna M Mattsson; Suvi Ravela; Can Hekim; Magnus Jonsson; Johan Malm; Ale Närvänen; Ulf-Håkan Stenman; Hannu Koistinen Journal: PLoS One Date: 2014-09-19 Impact factor: 3.240