Insulin-like growth factor binding proteins (IGFBPs) as potential physiological substrates for human kallikreins hK2 and hK3

Insulin-like growth factors (IGFs) are important growth regulators of both normal and malignant prostate cells. Their action is regulated by six insul in-like growth factor binding proteins (IGFBPs). The proteolytic cleavage o f IGFBPs by various proteases decreases dramatically their affinity for the ir ligands and therefore enhances the bioavailability of IGFs. To elucidate the putative biological role of prostatic kallikreins hK2 and hK3 (prostat e-specific antigen) in tumour progression, we analyzed the degradation of I GFBP-2, -3, -4 and -5 by these two tissue kallikreins. We found that hK3, a lready characterized as an IGFBP-3 degrading protease, cleaved IGFBP-4 but not IGFBP-2 and -5, whereas hK2 cleaved all of the IGFBPs much more effecti vely, and at concentrations far lower than those reported for other IGFBP-d egrading proteases. The proteolytic patterns after cleavage of IGFBPs by hK 2 and hK3 were similar and were not modified in the presence of IGF-I. Hepa rin, but not other glycosaminoglycans, enhanced dramatically the ability of hK3 but not hK2 to degrade IGFBP-3 and IGFBP-4. More importantly, the IGFB P fragments generated by hK2 and hK3 had no IGF-binding capacity, as assess ed by Western ligand blotting. Our results suggest that the prostatic kalli kreins hK2 and hK3 may influence specifically the tumoral growth of prostat e cells through the degradation of IGFBPs, to increase IGF bioavailability.