JPOST Repositoryapplication/xmlhttps://storage.jpostdb.org/JPST002261/files/230210-LNCaP%20(human%20full).xlsxhttps://storage.jpostdb.org/JPST002261/files/230210-DU145%20(human%20full).xlsxhttps://storage.jpostdb.org/JPST002261/files/121102-Urology-8%20(PC3_1).rawhttps://storage.jpostdb.org/JPST002261/files/121102-Urology-25%20(LNCaP_3).rawhttps://storage.jpostdb.org/JPST002261/files/121102-Urology-13%20(LNCaP_2).rawhttps://storage.jpostdb.org/JPST002261/files/121102-Urology-21%20(Du145_3).rawhttps://storage.jpostdb.org/JPST002261/files/121102-Urology-9%20(Du145_1).rawhttps://storage.jpostdb.org/JPST002261/files/121102-Urology-23%20(PC3_3).rawhttps://storage.jpostdb.org/JPST002261/files/121102-Urology-20%20(PC3_2).rawhttps://storage.jpostdb.org/JPST002261/files/121102-Urology-19%20(Du145_2).rawhttps://storage.jpostdb.org/JPST002261/files/121102-Urology-7%20(LNCaP_1).rawhttps://storage.jpostdb.org/JPST002261/files/121102-Urology-9%20(Du145_1)_mgf.mgfhttps://storage.jpostdb.org/JPST002261/files/121102-Urology-7%20(LNCaP_1)_mgf.mgfhttps://storage.jpostdb.org/JPST002261/files/121102-Urology-8%20(PC3_1)_mgf.mgfhttps://storage.jpostdb.org/JPST002261/files/121102-Urology-23%20(PC3_3)_mgf.mgfhttps://storage.jpostdb.org/JPST002261/files/121102-Urology-21%20(Du145_3)_mgf.mgfhttps://storage.jpostdb.org/JPST002261/files/121102-Urology-20%20(PC3_2)_mgf.mgfhttps://storage.jpostdb.org/JPST002261/files/121102-Urology-19%20(Du145_2)_mgf.mgfhttps://storage.jpostdb.org/JPST002261/files/121102-Urology-25%20(LNCaP_3)_mgf.mgfhttps://storage.jpostdb.org/JPST002261/files/121102-Urology-13%20(LNCaP_2)_mgf.mgfprimary200OKProteomicsNoriaki ArakawaHomo Sapiens (human)https://repository.jpostdb.org/entry/JPST002261National Institute of Health Sciences, JapanjPOST<h4>Background</h4>Bone metastasis (BM) is a common and fatal condition in patients with castration-resistant prostate cancer (CRPC). However, there are no useful blood biomarkers for CRPC with BM, and the mechanism underlying BM is unclear. In this study, we investigated precise blood biomarkers for evaluating BM that can improve the prognosis of patients with CRPC.<h4>Methods</h4>We comprehensively examined culture supernatants from four prostate cancer (PCa) cell lines using Orbitrap mass spectrometry to identify specific proteins secreted abundantly by PCa cells. The effects of this protein to PCa cells, osteoblasts, osteoclasts were examined, and BM mouse model. In addition, we measured the plasma concentration of this protein in CRPC patients for whom bone scan index (BSI) by bone scintigraphy was performed.<h4>Results</h4>A total of 2,787 proteins were identified by secretome analysis. We focused on GDF15 propeptide (GDPP), which is secreted by osteoblasts, osteoclasts, and PCa cells. GDPP promoted the proliferation, invasion, and migration of PC3 and DU145 CRPC cells, and GDPP aggravated BM in a mouse model. Importantly, GDPP accelerated bone formation and absorption in the bone microenvironment by enhancing the proliferation of osteoblasts and osteoclasts by upregulating individual transcription factors such as RUNX2, OSX, ATF4, NFATc1, and DC-STAMP. In clinical settings, including a total of 416 patients, GDPP was more diagnostic of BM than prostate-specific antigen (PSA) (AUC = 0.92 and 0.78) and the seven other blood biomarkers (alkaline phosphatase, lactate dehydrogenase, bone alkaline phosphatase, tartrate-resistant acid phosphatase 5b, osteocalcin, procollagen I N-terminal propeptide and mature GDF15) in patients with CRPC. The changes in BSI over time with systemic treatment were correlated with that of GDPP (r = 0.63) but not with that of PSA (r = -0.16).<h4>Conclusions</h4>GDPP augments the tumor microenvironment of BM and is a novel blood biomarker of BM in CRPC, which could lead to early treatment interventions in patients with CRPC.GDF15 propeptide promotes bone metastasis of castration-resistant prostate cancer by augmenting the bone microenvironment.Yamamichi Gaku G, Kato Taigo T, Arakawa Noriaki N, Ino Yoko Y, Ujike Takeshi T, Nakano Kosuke K, Koh Yoko Y, Motoyama Yuichi Y, Outani Hidetatsu H, Myoba Shohei S, Ishizuya Yu Y, Yamamoto Yoshiyuki Y, Hatano Koji K, Kawashima Atsunari A, Fukuhara Shinichiro S, Uemura Hiroji H, Okada Seiji S, Morii Eiichi E, Nonomura Norio N, Uemura Motohide Mhereditary prostate cancer, Bones and Bone Tissue, cancer of the prostate, osteogenic tissue., Apophyses, Prostate Neoplasms, Neoplasms, familial, Bones and Bone, Bone and Bone, Prostatic Cancer, Neoplasm, Prostatic Cancers, PTGFB, metastasis to bone, NOS, bones, PLAB, Cancer of Prostate, Gonadectomies, Gonadectomy, Prostate Cancers, Bone Tissues, Castrations, osseous tissue, Tissues, MIC1, portion of bone tissue, Tissue, PDF, MIC-1, Cancers, Condyle, Bones, cancer of prostate, Prostate Neoplasm, Prostatic Neoplasm, mineralized bone tissue, Cancer of the Prostate, Bony, Bone Tissue, bone, GDF-15, NAG-1, Prostatic, prostate cancer, Condyles, PC, calcium tissue, Apophysis, Bony Apophysis, bone organ, Prostate Cancer, Bony Apophyses, Bone, Prostate, CancerDimethylketon, Serum Free Media, prostate cancer cell, determination, Serum-Free, dimethylketone, Proteins, total expressed protein, Gene, Culture Media, Carbamide, Basodexan, ur, Aceton, Karbamid, 2-Propanone, carbamide, propanone, Media, Pyroacetic ether, carbonyldiamide, prostate tumour cell, Harnstoff, Protein, dimethylcetone, Gene Products, Protein-Free Media, Carmol, methyl ketone, uree, E927b, Serum-Free Culture, chemical analysis., Serum-Free Culture Media, beta-Ketopropane, Protein Free Media, Serum-Free Media, Protein Gene Products, Low-Serum Media, Gene Proteins, prostate tumor cell, H2NC(O)NH2, Serum Free, Propanon, Low Serum Media, assay, Azeton, Dimethyl ketone, Low-Serum, 1728, Proteomes, prostate carcinoma cell, Protein-Freeprimary cancer, Secretomes, Malignant Neoplasm, Malignancy, Protein., Neoplasms, Benign Neoplasm, Protein Secretomes, Benign Neoplasms, Cancers, Tumor, Malignant, malignant tumor, Malignant Neoplasms, Neoplasias, MT, Benign, malignant neoplasm, Secretome, Protein, Neoplasm, Protein Secretome, Malignancies, Neoplasia, Cancer, Tumorsccd, Polycomb 3 homolog, Surrogate Endpoints, Bone 4-Carboxyglutamic Protein, Laboratory, Gamma Camera Imaging, Phosphatase, Ossification, Tartrate Resistant Acid Phosphatase, Tumor, House Mouse, Long Term, RC1, Orthophosphoric-monoester phosphohydrolase (alkaline optimum), Physiological Ossification, Biological, Method, Cultural, Att-1, Line, 1, KLK2A1, Analysis, Bone Gla Protein, Tumor Microenvironments, Fs(3)Hor, Benson syndrome, Atf4, Bone Tissues, 929, DmelCG8669, treatment, amyloidosis, Fresh Frozen, ethnicity, Analyses, NFATc1, An, Tartrate-Resistant Acid Phosphatase Type 5, Tissue, V, procedures, K6A, K6D, K6C, NLS2, NTef2, APase, R74825, NEC1, bone biosynthesis, goku, Cementoclasts, Cancer of the Prostate, Nec-1, Condyles, Homo sapiens disease, Bony Apophyses, plasma, Physiological, Protocollagen, Pc3, ccd1, Viral, OSF-2, PC-3 cell, Pdnp1, Atf-4, 2310009M18Rik, familial, arteria cerebri communicans posterior, CORD19, Longterm Effect, familial cutaneous lichen, Procedure, Spectrum Analysis, Fs(3)Sz11, PC3, Cultural Background, 4833416E15Rik, Cultures, Marker, Pca, PCA, CTRN2, l(2)crc, APRO1, Rectachrome 1, PCS, mPc3, Acid, NFAT transcription complex cytosolic component, End Points, Cultural Beliefs, Endochondral Ossifications, Swiss Mouse, Spectrometry, CCD1, Protein Secretomes, PDF, C|ATF, Prostate Specific Antigen, Immunologic, Methodological, Laboratory Marker, znfxy, cancer of prostate, ATF-4, Bone gamma-Carboxyglutamic Acid Protein, Agl, gbbb1, CG2684, Mouse, pebp2aa1, Bony Apophysis, ATF4/crc, Vitamin K-Dependent, PSATD, Fresh, mKIAA0998, RNF59, Fresh Frozen Plasma, CREB-2, Effects, MP100, Dehydrogenase, Clinical Marker, Neoplasms, psoriatic arthropathy, MIDIN, pebp2a1, Prognostic Factors, protein-containing complex, Transcription Factor, Kal3, AcPase V, Type 5 Acid Phosphatase, Duke University 145, CK6D, CK6C, Cancer Microenvironment, CK6A, L Lactate Dehydrogenase, Gene Products, disease or disorder, Mus musculus domesticus, GBBB1, Cancer of Prostate, bone formation, Technique, Backgrounds, Passive Cutaneous, pebp2aa, Transcription, osf2, Vitamin K Dependent, Clinical, Longterm, Tissues, PSAT, Cultural Relativisms, Long-Term, Calcium-Binding Protein, OI12, OI11, Study, 2210017P03Rik, 1700048H13Rik, D8Ertd814e, Cementoclast, Vitamin K Dependent Bone Protein, pebp2a2, Prostatic, Customs, MFSD7B, Apophysis, Biologic, Bone Formation, Cancer, hereditary prostate cancer, Secretomes, Apophyses, whole blood, Serum Markers, Proteins, disorders, Kal-3, nf-atc, Factor, Cultural Backgrounds, Endochondral Ossification, AI449492, Cell, phoA, Immune Marker, trim18, 3-de-L-tyrosine-4-de-L-glutamine-5-de-L-tryptophan-6-de-L-leucine-9-L-serine-12-L-serine-19-L-threonine-22-L-glutamine-28-L-alanine-33-L-serine-35-L-glutamine-36-L-tyrosine-38-L-leucine-39-L-lysine-40-L-threonine-43-L-lysine-45-L-isoleucine-48-L-isoleucine-49-L-threonine-49a-L-isoleucine-, Bones and Bone, Frozen Plasmas, M6S1, MS, native protein, Surrogate End Point, susceptibility to psoriatic arthritis, Prostatic Cancer, chemical analysis, Long Term Effects, Neoplasm, Psat, Tartrate-Resistant, condition, NFATc, Osf2, OSF2, Odontoclasts, Mass Spectrum Analyses, Physiologic Ossification, Biologic Markers, ogs1, C22, Semenogelase, Castrations, osseous tissue, FXY, Surrogate, NFAT2, Endpoints, choanal atresia, NF-ATC, NFATC, House Mice, TRAcP, Cancers, CBFA1, Odontoclast, Bones, Lds, Ossifications, Longterm Effects, bbbg1, 4 Carboxyglutamic Protein, Gene Proteins, TAXREB67, OS, L-Lactate, mineralized bone tissue, fxy, NAG-1, prostate cancer, Relativisms, NF-ATc, PC, calcium tissue, Bone Gla, ttw, Relativism, Cultural Relativism, bone organ, Microenvironments, Immune Markers, Bones and Bone Tissue, Scanning, APS, Biological Markers, Viral Marker, determination, Blood, AI428864, Mus domesticus, Radioisotope Scanning, Biochemical, Endpoint, Imaging, protein, Serum, BSI, osteogenic tissue, Laboratory Markers, Techniques, Background, Bone and Bone, diseases, Cbfa1, Secretome, 6430578P22Rik, PTGFB, OGS1, diseases and disorders, TRIM18, Acid Phosphatase, protein aggregate, Effect, Kallikrein-3, gamma-Seminoprotein, Gonadectomies, Mass Spectrum Analysis, Fresh Frozen Plasmas, AAP-S, human disease, DmelCG2684, Prognoses, Pca-1, Klk3, osteogenesis, MIC-1, Swiss Mice, twy, SCAN, aml3, Prostatic Neoplasm, Immune, 4-Carboxyglutamic Protein, Markers, Methodological Studies, Viral Markers, GDF-15, hK3 Kallikrein, disease management, Therapies, Gla Protein, house mouse, Acid Phosphatase V, Pebp2a1, Long-Term Effects, Cancer Microenvironments, Therapy, cancer of the prostate, CBF-alpha-1, Uteroferrin, Frozen Plasma, THPH5, Surrogate Endpoint, Radioisotope, THPH6, Osteocalcin (human reduced), AML3, mouse, R75373, CLCD, Biochemical Markers, D630041K24Rik, Biologic Marker, Plasmas, AA959598, PSA, Psa, Spectroscopy, NF-ATc1, C76301, POSTERIOR, NOS, Osteoclastogeneses, PEBP2aA, ZNF912, AXPC1, psoriatic arthritis, an-1, Lines, Mus musculus, Factors, mice, Prognostic, portion of bone tissue, MIC1, susceptibility to, Radionuclide, KIAA0998, Anaphylaxis, gamma Seminoprotein, Bone 4-Carboxyglutamic, Condyle, Methodological Study, Treatments, early, domesticus, disease, Bony, Patient, Biochemical Marker, bone, Horka, Fs(3)Horka, PC-1, CG8669, OSX, Osx, Seminin, Ly-41, Bone, PC-3, Prostate, Prognostic Factor, other disease, Passive, CD203c, XPRF, NPP1, Procedures, Gamma-seminoprotein, Prostate Neoplasms, ARP1B, Clinical Markers, Scintigraphy, ZNFXY, Microenvironment, TRAP Type 5 AcPase, osterix, Gene, xprf, osx, Tartrate-Resistant Acid, Spectrum Analyses, STAMP, KRT6D, KRT6C, Surrogate End Points, Surrogate Markers, Client., hPc3, PEA2aA, dATF-4, House, Prostatic Cancers, Studies, Mass, Osteoclastogenesis, metastasis to bone, EPIP, Scintiphotography, DmF2, PLAB, Mice, Mass Spectroscopy, Vitamin K-Dependent Bone Protein, Prostate Cancers, Npps, Calcium Binding Protein, lod, FLVCR, Biomarker, study, PROS, Blood Plasma, Phosphatase V, Osteoclast, Swiss, Physiologic, Biological Marker, biparietal Alzheimer disease, Nfatcb, P-30 antigen, Cytosol alanyl aminopeptidase, Ire1, 4930556H18Rik, lichen amyloidosis, midin, Tartrate Resistant Acid Phosphatase Type 5, non-neoplastic, RCB2143, SGPA, Stamp, Immunologic Markers, Pebpa2a, Kallikrein, Bone gamma Carboxyglutamic Acid Protein, Clients, Kallikrein hK3, Blood Plasmas, disorder, (S)-Lactate:NAD+ oxidoreductase, Long-Term Effect, culture, Cbfa-1, Immunologic Marker, PC3 cell, Lactate, protein complex, LS3, BBBG1, Cell Lines, End Point, medical condition, Endochondral, 3.4.11.14, nfat2, Client, pea2aa, Cutaneous Anaphylaxis, PS24, PS23, TXREB, PS25, DU145, PS22, PS21, Mus, AI428932, Protein, CREB2, hK3, Gamma Camera, techniques, bones, cbfa1, rnf59, Gonadectomy, Plasma, Mass Spectrum, Serum Marker, Cbf, 3.4.21.77, portion of plasma, Osteoblast, Surrogate Marker, Prostate Neoplasm, Laboratory Mice, Protein Gene Products, CCD, nfatc, AcPase, Bone Tissue, Lactate Dehydrogenase, Therapeutic, PCARP, concentration, Indexes, Tis21, Protein Secretome, Treatment, assay, E-NPP1, Procollagen Type M, Prostate Cancer, DU-145, Laboratory Mouse, AV076380, methodology, TIS21falseIdentification of GDPP in cancer secretomeProstate cancer cell lines were cultured with serum-free media, for 48 h. The cultured media were collected and lyophilized. The lyophilized media were dissolved in ammonium bicarbonate containing 4 M urea, and proteins were de-salted by acetone-precipitation and subjected to proteome analysis.Wed Jan 01 00:00:00 GMT 2025PXD045369960639587633