Prostate-specific antigen enhances bioavailability of insulin-like growth factor by degrading insulin-like growth factor binding protein 5.

In the bone matrix, insulin-like growth factors (IGFs) are the most abundant growth factors and IGF binding protein 5 (IGFBP-5) is the major IGFBP. Our previous study suggested that IGFs stored in the bone matrix and prostate-specific antigen (PSA) play an important role in prostate cancer (PC) bone metastasis. However, it is not clear how IGF signaling is activated in the bone microenvironment of PC metastasis. Therefore, we investigated whether PSA degrades IGFBP-5 and enhances biological activity of IGF. Enzymatically active PSA degraded the recombinant IGFBP-5 protein in a dose- and time-dependent manner and a serine protease inhibitor suppressed this degradation. Furthermore, PSA induced IGF-mediated type I IGF receptor phosphorylation that was inhibited by coincubation with IGFBP-5. The present study indicates PSA derived from PC cells can enhance IGF bioavailability in the bone microenvironment of PC metastasis, thereby permitting PC survival and malignant progression in the bone microenvironment.

[1]  N. Kanomata,et al.  Osteoprotegerin/osteoclastogenesis inhibitory factor decreases human prostate cancer burden in human adult bone implanted into nonobese diabetic/severe combined immunodeficient mice. , 2003, Cancer research.

[2]  T. Oda,et al.  Prostate-specific antigen induces osteoplastic changes by an autonomous mechanism. , 2001, Biochemical and biophysical research communications.

[3]  T. Christmas,et al.  Inverse relation between prostate-specific antigen and insulin-like growth factor-binding protein 3 in bone metastases and serum of patients with prostate cancer , 1999, The Lancet.

[4]  G. Yousef,et al.  The new human tissue kallikrein gene family: structure, function, and association to disease. , 2001, Endocrine reviews.

[5]  L. Giudice,et al.  Prostate-specific antigen (PSA) is an insulin-like growth factor binding protein-3 protease found in seminal plasma. , 1992, The Journal of clinical endocrinology and metabolism.

[6]  H. Senn,et al.  Insulin-like growth factors and cancer. , 2002, The Lancet. Oncology.

[7]  R. Baxter,et al.  Cellular actions of the insulin-like growth factor binding proteins. , 2002, Endocrine reviews.

[8]  V. Hwa,et al.  The Insulin-like Growth Factor-binding Protein (igfbp) Superfamily* , 2022 .

[9]  D. Clemmons,et al.  Insulin-like growth factor-binding protein-5 is cleaved by physiological concentrations of thrombin. , 1998, Endocrinology.

[10]  P. Cohen,et al.  Role of insulin‐like growth factors and their binding proteins in growth control and carcinogenesis , 2000, Journal of cellular physiology.

[11]  P. Monget,et al.  Insulin-like growth factor binding proteins (IGFBPs) as potential physiological substrates for human kallikreins hK2 and hK3. , 2001, European journal of biochemistry.

[12]  N. Kanomata,et al.  Establishment of a novel species- and tissue-specific metastasis model of human prostate cancer in humanized non-obese diabetic/severe combined immunodeficient mice engrafted with human adult lung and bone. , 2001, Cancer research.

[13]  C. Conover,et al.  Pregnancy-associated Plasma Protein-A2 (PAPP-A2), a Novel Insulin-like Growth Factor-binding Protein-5 Proteinase* , 2001, The Journal of Biological Chemistry.

[14]  W. M. Linehan,et al.  Metastatic models and molecular genetics of prostate cancer. , 1992, Journal of the National Cancer Institute.

[15]  T. Stamey,et al.  Prostate-Specific Antigen as a Serum Marker for Adenocarcinoma of the Prostate , 1987 .

[16]  S. Mohan,et al.  An age-related decrease in the concentration of insulin-like growth factor binding protein-5 in human cortical bone , 1995, Calcified Tissue International.

[17]  K. Shitara,et al.  Growth Inhibition of Human Prostate Cancer Cells in Human Adult Bone Implanted into Nonobese Diabetic/Severe Combined Immunodeficient Mice by a Ligand-Specific Antibody to Human Insulin-Like Growth Factors , 2004, Cancer Research.

[18]  D. Clemmons,et al.  Protease-resistant form of insulin-like growth factor-binding protein 5 is an inhibitor of insulin-like growth factor-I actions on porcine smooth muscle cells in culture. , 1997, The Journal of clinical investigation.

[19]  S. Hankinson,et al.  Insulin-like growth factors and neoplasia , 2004, Nature Reviews Cancer.