NKX3.1 activates expression of insulin-like growth factor binding protein-3 to mediate insulin-like growth factor-I signaling and cell proliferation.

NKX3.1 is a homeobox gene that codes for a haploinsufficient prostate cancer tumor suppressor. NKX3.1 protein levels are down-regulated in the majority of primary prostate cancer tissues. NKX3.1 expression in PC-3 cells increased insulin-like growth factor binding protein-3 (IGFBP-3) mRNA expression 10-fold as determined by expression microarray analysis. In both stably and transiently transfected PC-3 cells and in LNCaP cells, NKX3.1 expression increased IGFBP-3 mRNA and protein expression. In prostates of Nkx3.1 gene-targeted mice Igfbp-3 mRNA levels correlated with Nkx3.1 copy number. NKX3.1 expression in PC-3 cells attenuated the ability of insulin-like growth factor-I (IGF-I) to induce phosphorylation of type I IGF receptor (IGF-IR), insulin receptor substrate 1, phosphatidylinositol 3-kinase, and AKT. The effect of NKX3.1 on IGF-I signaling was not seen when cells were exposed to long-R3-IGF-I, an IGF-I variant peptide that does not bind to IGFBP-3. Additionally, small interfering RNA-induced knockdown of IGFBP-3 expression partially reversed the attenuation of IGF-IR signaling by NKX3.1 and abrogated NKX3.1 suppression of PC-3 cell proliferation. Thus, there is a close relationship in vitro and in vivo between NKX3.1 and IGFBP-3. The growth-suppressive effects of NKX3.1 in prostate cells are mediated, in part, by activation of IGFBP-3 expression.

[1]  E. Gelmann,et al.  Inflammatory cytokines induce phosphorylation and ubiquitination of prostate suppressor protein NKX3.1. , 2008, Cancer research.

[2]  Derek Y. Chiang,et al.  Characterizing the cancer genome in lung adenocarcinoma , 2007, Nature.

[3]  C. Bieberich,et al.  Decreased NKX3.1 Protein Expression in Focal Prostatic Atrophy, Prostatic Intraepithelial Neoplasia, and Adenocarcinoma: Association with Gleason Score and Chromosome 8p Deletion , 2006 .

[4]  T. Ludwig,et al.  Diminished growth and enhanced glucose metabolism in triple knockout mice containing mutations of insulin-like growth factor binding protein-3, -4, and -5. , 2006, Molecular endocrinology.

[5]  N. Weigel,et al.  Role of insulin‐like growth factor binding proteins in 1α,25‐dihydroxyvitamin D3‐induced growth inhibition of human prostate cancer cells , 2005, The Prostate.

[6]  W. Willett,et al.  Plasma insulin-like growth factor-1 and binding protein-3 and subsequent risk of prostate cancer in the PSA era , 2005, Cancer Causes & Control.

[7]  E. Gelmann,et al.  Deletion, methylation, and expression of the NKX3.1 suppressor gene in primary human prostate cancer. , 2005, Cancer research.

[8]  B. G. Blijenberg,et al.  Circulating free insulin-like growth factor (IGF)-I, total IGF-I, and IGF binding protein-3 levels do not predict the future risk to develop prostate cancer: results of a case-control study involving 201 patients within a population-based screening with a 4-year interval. , 2004, The Journal of clinical endocrinology and metabolism.

[9]  P. Stattin,et al.  High levels of circulating insulin-like growth factor-I increase prostate cancer risk: a prospective study in a population-based nonscreened cohort. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

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

[11]  T. Peters,et al.  Screen‐detected prostate cancer and the insulin‐like growth factor axis: Results of a population‐based case‐control study , 2004, International journal of cancer.

[12]  J. Witte,et al.  Relation of serum insulin-like growth factor-I (IGF-I) and IGF binding protein-3 to risk of prostate cancer (United States) , 2003, Cancer Causes & Control.

[13]  D. Albanes,et al.  Serum insulin-like growth factor I: tumor marker or etiologic factor? A prospective study of prostate cancer among Finnish men. , 2003, Cancer research.

[14]  J. Miano,et al.  Serum response factor: toggling between disparate programs of gene expression. , 2003, Journal of molecular and cellular cardiology.

[15]  Jeffrey A. Magee,et al.  Haploinsufficiency at the Nkx3.1 locus. A paradigm for stochastic, dosage-sensitive gene regulation during tumor initiation. , 2003, Cancer cell.

[16]  M. Stampfer,et al.  Insulin-like growth factor-I (IGF-I) and IGF binding protein-3 as predictors of advanced-stage prostate cancer. , 2002, Journal of the National Cancer Institute.

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

[18]  T. Barrette,et al.  Meta-analysis of microarrays: interstudy validation of gene expression profiles reveals pathway dysregulation in prostate cancer. , 2002, Cancer research.

[19]  M. Rechler,et al.  Insulin-like Growth Factor (IGF)-binding Protein-3 Mutants That Do Not Bind IGF-I or IGF-II Stimulate Apoptosis in Human Prostate Cancer Cells* , 2002, The Journal of Biological Chemistry.

[20]  Peter A. Humphrey,et al.  Conditional Loss of Nkx3.1 in Adult Mice Induces Prostatic Intraepithelial Neoplasia , 2002, Molecular and Cellular Biology.

[21]  R. Cardiff,et al.  Cooperativity of Nkx3.1 and Pten loss of function in a mouse model of prostate carcinogenesis , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[22]  D. Bostwick,et al.  Determination of a minimal deletion interval on chromosome band 8p21 in sporadic prostate cancer † , 2002, Genes, chromosomes & cancer.

[23]  H. Koistinen,et al.  Prostate‐specific antigen and other prostate‐derived proteases cleave IGFBP‐3, but prostate cancer is not associated with proteolytically cleaved circulating IGFBP‐3 , 2002, The Prostate.

[24]  G E Walker,et al.  Butyrate, a histone deacetylase inhibitor, activates the human IGF binding protein-3 promoter in breast cancer cells: molecular mechanism involves an Sp1/Sp3 multiprotein complex. , 2001, Endocrinology.

[25]  T. Fears,et al.  Insulin-like growth factors and prostate cancer: a population-based case-control study in China. , 2001, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[26]  D. Ornstein,et al.  Expression studies and mutational analysis of the androgen regulated homeobox gene NKX3.1 in benign and malignant prostate epithelium. , 2001, The Journal of urology.

[27]  R. Schwartz,et al.  The Smooth Muscle γ-Actin Gene Promoter Is a Molecular Target for the Mouse bagpipe Homologue, mNkx3-1, and Serum Response Factor* , 2000, The Journal of Biological Chemistry.

[28]  E. Riboli,et al.  Plasma insulin-like growth factor-I, insulin-like growth factor-binding proteins, and prostate cancer risk: a prospective study. , 2000, Journal of the National Cancer Institute.

[29]  O. Kallioniemi,et al.  Loss of NKX3.1 expression in human prostate cancers correlates with tumor progression. , 2000, Cancer research.

[30]  E. Metter,et al.  Serum levels of insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-3, and prostate-specific antigen as predictors of clinical prostate cancer. , 2000, The Journal of clinical endocrinology and metabolism.

[31]  T. Wood,et al.  Selective alterations in organ sizes in mice with a targeted disruption of the insulin-like growth factor binding protein-2 gene. , 2000, Molecular endocrinology.

[32]  K. Devriendt,et al.  Deletion of NKX2.1 gene encoding thyroid transcription factor-1 in two siblings with hypothyroidism and respiratory failure. , 2000, The Journal of pediatrics.

[33]  E. Gelmann,et al.  DNA-binding sequence of the human prostate-specific homeodomain protein NKX3.1. , 2000, Nucleic acids research.

[34]  I. McCutcheon,et al.  The effects of insulin-like growth factors on tumorigenesis and neoplastic growth. , 2000, Endocrine reviews.

[35]  J. Seidman,et al.  Loss of function and inhibitory effects of human CSX/NKX2.5 homeoprotein mutations associated with congenital heart disease. , 2000, The Journal of clinical investigation.

[36]  J. Seidman,et al.  Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways. , 1999, The Journal of clinical investigation.

[37]  R. Cardiff,et al.  Roles for Nkx3.1 in prostate development and cancer. , 1999, Genes & development.

[38]  C. Sawyers,et al.  The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[39]  C. Mantzoros,et al.  Insulin-like growth factor 1 and prostate cancer risk: a population-based, case-control study. , 1998, Journal of the National Cancer Institute.

[40]  S. Mohan,et al.  Insulin-like growth factor-binding proteins in serum and other biological fluids: regulation and functions. , 1997, Endocrine reviews.

[41]  M. Augustus,et al.  Coding region of NKX3.1, a prostate-specific homeobox gene on 8p21, is not mutated in human prostate cancers. , 1997, Cancer research.

[42]  S. Mohan,et al.  Insulin‐Like Growth Factor (IGF) System Components in Human Prostatic Cancer Cell‐Lines: LNCaP, DU145, and PC‐3 Cells , 1996, International journal of urology : official journal of the Japanese Urological Association.

[43]  D. Leroith,et al.  The Role of the Tyrosine Kinase Domain of the Insulin-like Growth Factor-I Receptor in Intracellular Signaling, Cellular Proliferation, and Tumorigenesis (*) , 1995, The Journal of Biological Chemistry.

[44]  D. Clemmons,et al.  Insulin-like growth factors and their binding proteins: biological actions. , 1995, Endocrine reviews.

[45]  A. Sommer,et al.  Biochemical analysis of prostate specific antigen-proteolyzed insulin-like growth factor binding protein-3. , 1994, Growth regulation.

[46]  D. Peehl,et al.  Biological effects of prostate specific antigen as an insulin-like growth factor binding protein-3 protease. , 1994, The Journal of endocrinology.

[47]  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.

[48]  J. Wallace,et al.  Novel recombinant fusion protein analogues of insulin-like growth factor (IGF)-I indicate the relative importance of IGF-binding protein and receptor binding for enhanced biological potency. , 1992, Journal of molecular endocrinology.

[49]  J. Wallace,et al.  Production and characterization of recombinant insulin-like growth factor-I (IGF-I) and potent analogues of IGF-I, with Gly or Arg substituted for Glu3, following their expression in Escherichia coli as fusion proteins. , 1992, Journal of molecular endocrinology.

[50]  Jianfeng Xu,et al.  Germ-line mutation of NKX3.1 cosegregates with hereditary prostate cancer and alters the homeodomain structure and function. , 2006, Cancer research.

[51]  Noel S Weiss,et al.  Prostate carcinoma incidence in relation to prediagnostic circulating levels of insulin‐like growth factor I, insulin‐like growth factor binding protein 3, and insulin , 2005, Cancer.

[52]  M. Stampfer,et al.  Insulin-like growth factor-I (IGF-I) and IGF binding protein-3 as predictors of advanced-stage prostate cancer. , 2002, Journal of the National Cancer Institute.

[53]  E. Ludolphy.  [Cancer cells]. , 1950, Medizinische Monatsschrift.