MassIVEapplication/xmlftp://massive-ftp.ucsd.edu/x01/MSV000080734/primary200OK0000Christopher Gernerhttps://massive.ucsd.edu/ProteoSAFe/dataset.jsp?task=87ab921a1d75485ab9ed8297b9e304d9christopher.gerner@univie.ac.atMassIVE37UNIMOD:4 - "Iodoacetamide derivative."UNIMOD:1 - "Acetylation."UNIMOD:35 - "Oxidation or Hydroxylation."ProteomicsQ ExactiveHomo Sapiens (ncbitaxon:9606)University of Vienna, Faculty of Chemistry, Department of Analytical ChemistryResponse profiling using shotgun proteomics for establishing global metallodrug mechanisms of action in two colon carcinoma cell lines, HCT116 and SW480, has been applied and evaluated with the clinically approved arsenic trioxide. Surprisingly, the complete established mechanism of action of arsenic trioxide was observed by protein regulations in SW480, but not HCT116 cells. Comparing the basal protein expression in the two cell lines revealed an 80 % convergence of protein identification, but with significant expression differences, which in turn seem to affect the extent of protein regulation. A clear-cut redox response was observed in SW480 cells upon treatment with arsenic, but hardly in HCT116 cells. Response profiling was then used to investigate four anti-cancer metallodrugs (KP46, KP772, KP1339 and KP1537). Proteome alterations were mapped to selected functional groups, including DNA repair, endocytosis, protection from oxidative stress, protection from endoplasmatic reticulum (ER) stress, cell adhesion and mitochondrial function. The present data suggest that knowledge of the mechanism of action of anti-cancer metallodrugs and improved patient stratification strategies are imperative for the design of clinical studies.Response Profiling Using Shotgun Proteomics Enables Global Metallodrug Mechanisms of Action To Be Established.Kreutz Dominique D, Bileck Andrea A, Plessl Kerstin K, Wolrab Denise D, Groessl Michael M, Keppler Bernhard K BK, Meier Samuel M SM, Gerner Christopher CTransitional Epithelial Cell, Transitional, Adenomatous Epithelial Cell, reactivity, Squamous Cells, Adenomatous Epithelial Cells, Squamous Cell, Epithelial Cell, Peptidomics, Glandular Epithelial Cell., Proteins, Glandular Epithelial Cells, Adenomatous, Gene, KP1339, Adenomatous Epithelial, Glandular Epithelial, Squamous, Glandular, Transitional Epithelial, sodium trans-(tetrachlorido-bis(1H-indazole)ruthenate(III)), Cell, Protein Gene Products, Gene Proteins, Squamous Epithelial Cells, Cuboidal Glandular Epithelial Cells, Epithelial Cells, Transitional Epithelial Cells, responsivity, Protein, Cells, Gene Products, SW480, BOLD-100, response, Columnar Glandular Epithelial Cells, KP-1339, SW480E, Squamous Epithelial Cell, Squamous Epithelial, Epithelialextent, Regulations, DNA Oxidative, arsenicum, Oxidative Stress, l(1)VE614, HCT116, Peptidomics, Anhydride arsenieux, carcinoma cell, Antioxidative, Arsenolite, Antioxidative Stress, Gene, Nitrative Stress, Endocytoses, colon carcinoma cell, protein, nonselective vesicle endocytosis, protein-containing complex, HCT-116 Cells, mitochondrial, Damage, Social Controls, Arsenic-75, Stresses, Cut, protein polypeptide chains, Arsenic blanc, Client., Oxidative Nitrative, polypeptide chain, Oxidative DNA, l(1)7Ba, Oxidative, Stress Injury, l(1)7Bb, Taenia Coli, responsivity, As2O3, Nitro-Oxidative Stress, Appendix, Gene Products, Line, DNA Damage Response, Oxidative Cleavages, Mood, BOLD-100, Nitro-Oxidative Stresses, single organism cell adhesion, HCT116 Cell, protein aggregate, Oxidative Injury, Formal Social Controls, DNA Damage, Oxidative Damages, treatment, reactivity, Arsenic, Oxidative Injuries, Omental Appendix, Injury, Diarsenic Trioxide, Moods, cell adhesion molecule activity, Oxidative Cleavage, As, Tetra Arsenic Hexaoxide, posterior intestine, Arsenous oxide anhydride, proteins, Tetra-Arsenic Oxide, Oxidative DNA Damages, kf, sodium trans-(tetrachlorido-bis(1H-indazole)ruthenate(III)), CG11387, Anti-oxidative, Social, Adhesions, Oxidative Stress Injuries, Oxidative Stresses, DmelCG11387, Anti oxidative Stress, Arsenic trioxide, Oxidative DNA Damage, Antioxidative Stresses, Clients, Adhesion, disease management, Therapies, CT, HCT 116 Cell, SW480E, Trixenox, Trisenox, Therapy, plasma membrane invagination, completeness, Formal Social Control, Tetra-Arsenic Hexaoxide, protein complex, Affects, Proteins, Ct, Cell Lines, total expressed protein, KP1339, function, Anti-oxidative Stresses, Appendix Epiploica, Cell, hindgut, As4O6, Arsen, HCT116 cell, Oxidative Nitrative Stress, 33As, large bowel, native protein, natural protein, ATP synthase D chain, Social Control, Oxidative and Nitrosative Stress, arsenic, Oxidative Nitrative Stresses, Naonobin, Protein, arsenic(III) oxide, Arsenic(III) Oxide, Arsenous oxide, DNA Oxidative Damages, BcDNA:GH10590, Arsenous Anhydride, Omental Appendices, Arsenic Oxide (As2O3), Lines, Arsenic Oxide (As4O6), Mitochondrial, Epistemology, HCT-116 Cell, Anti-oxidative Stress, HCT-116, DNA Oxidative Damage, HCT 116 Cells, Control, Tetraarsenic Hexaoxide, Diarsenic oxide, Appendices, Cell Adhesions, Arsenigen saure, patient, Omental, Controls, Cleavage, colonic carcinoma cell, Arsenic 75, Treatments, Protein Gene Products, Nitro-Oxidative, Gene Proteins, clear, hyaline, Therapeutic, Patient, COLON, HCT 116, Acide arsenieux, Cells, Stress, SW480, arsenico, Treatment, Oxidative Stress Injury, HCT-116 cell, regulation, response, Tetra Arsenic Oxide, DNA, colon, KP-1339, Nitro Oxidative Stress, Reticulums, Regulation, White arsenic, Proteomes, colon cancer cell, Tetraarsenic Oxide, Oxidative DamageAction, Generic Action., PeptidomicsDNA Oxidative, mode of action, arsenicum, pharmacodynamics, HCT116, carcinoma cell, Arsenolite, Nitrative Stress, protein, nonselective vesicle endocytosis, Tumor, HCT-116 Cells, Damage, Social Controls, Cut, protein polypeptide chains, Generic Action, Arsenic blanc, judicial aspects, Oxidative DNA, l(1)7Ba, Oxidative, l(1)7Bb, As2O3, Nitro-Oxidative Stress, Line, BOLD-100, Nitro-Oxidative Stresses, protein aggregate, Oxidative Injury, Formal Social Controls, DNA Damage, treatment, Oxidative Injuries, Moods, Oxidative Cleavage, medicolegal aspects, As, Arsenous oxide anhydride, proteins, Oxidative DNA Damages, sodium trans-(tetrachlorido-bis(1H-indazole)ruthenate(III)), CG11387, Anti-oxidative, Social, Adhesions, Oxidative Stress Injuries, Oxidative Stresses, malignant neoplasm, Adhesion, disease management, Therapies, CT, Malignancies, juridical aspects, HCT 116 Cell, Trixenox, Tumors, Trisenox, Therapy, Ct, KP1339, As4O6, HCT116 cell, 33As, Benign, Redox, ATP synthase D chain, Oxidative and Nitrosative Stress, arsenic, arsenic(III) oxide, Arsenic(III) Oxide, DNA Oxidative Damages, BcDNA:GH10590, Arsenous Anhydride, Lines, Action, Arsenic Oxide (As4O6), Mitochondrial, Epistemology, HCT-116, jurisprudence, HCT 116 Cells, Control, Tetraarsenic Hexaoxide, Benign Neoplasms, Arsenigen saure, Controls, Treatments, Malignant Neoplasms, Nitro-Oxidative, hyaline, Patient, Acide arsenieux, Cells, arsenico, Oxidative Stress Injury, litigation, Tetra Arsenic Oxide, DNA, colon, Reticulums, Regulation, White arsenic, Proteomes, colon cancer cell, Oxidation Reduction, Oxidative Damage, Regulations, Oxidative Stress, l(1)VE614, ordinances, Peptidomics, Anhydride arsenieux, Antioxidative, Neoplasms, Benign Neoplasm, Antioxidative Stress, Gene, Endocytoses, colon carcinoma cell, protein-containing complex, Malignant, mitochondrial, Arsenic-75, Stresses, legislation and jurisprudence, laws, civil suits, Client., Oxidative Nitrative, polypeptide chain, Stress Injury, Gene Products, DNA Damage Response, Oxidative Cleavages, Mood, single organism cell adhesion, HCT116 Cell, Oxidative Damages, Arsenic, Injury, Malignancy, Diarsenic Trioxide, cell adhesion molecule activity, Tetra Arsenic Hexaoxide, Tetra-Arsenic Oxide, kf, Neoplasias, mechanism of action, DmelCG11387, Anti oxidative Stress, Arsenic trioxide, Oxidative DNA Damage, Antioxidative Stresses, Clients, lawsuits, regulations, statutes, SW480E, Cancer, Malignant Neoplasm, plasma membrane invagination, Formal Social Control, Tetra-Arsenic Hexaoxide, protein complex, Affects, Proteins, Cell Lines, total expressed protein, function, Anti-oxidative Stresses, Cell, Arsen, Oxidative Nitrative Stress, MT, native protein, natural protein, Social Control, government regulations, Oxidative Nitrative Stresses, Naonobin, Protein, Neoplasm, Arsenous oxide, legal aspects, Arsenic Oxide (As2O3), HCT-116 Cell, primary cancer, Anti-oxidative Stress, DNA Oxidative Damage, Diarsenic oxide, Cell Adhesions, patient, Cancers, Cleavage, colonic carcinoma cell, Arsenic 75, malignant tumor, court decisions, Protein Gene Products, Gene Proteins, pharmacologic action, clear, Therapeutic, HCT 116, Stress, SW480, Treatment, HCT-116 cell, regulation, KP-1339, Nitro Oxidative Stress, Neoplasia, Tetraarsenic Oxide0PXD004778trueResponse Profiling Using Shotgun Proteomics Enables Establishing Global Metallodrug Mechanisms of Action - cytoplasmic proteins of KP1339-treated SW480 epithelial cellsResponse profiling using shotgun proteomics for establishing global metallodrug mechanisms of action in two colon carcinoma cell lines, HCT116 and SW480, was applied and evaluated with the clinically approved arsenic trioxide. Surprisingly, the complete established mechanism of action of arsenic trioxide was observed by protein regulations in SW480, but not in HCT116 cells. Comparing the basal protein expression in the two cell lines revealed an 80% convergence of protein identifications, but with significant expression differences, which in turn seem affect the extent of protein regulation. For example, while a clear-cut redox response was observed in SW480 cells upon arsenic treatment, such an effect was lacking in HCT116 cells and the latter express drastically higher levels of the involved redox proteins. Response profiling was then used to investigate four anticancer metallodrugs (KP46, KP772, KP1339 and KP1537) by means of functional groups of proteins and mapped their effects according to DNA repair, endocytosis, protection from oxidative stress, protection from endoplasmatic reticulum (ER) stress, cell adhesion and mitochondrial function. We were able to characterize the global effects of these metallodrugs on the proteome and generate hypotheses on hitherto unrecognized mechanisms. Significant differences in the two colon cell lines strongly suggest that knowledge of mechanistic hallmarks of anticancer metallodrug action are imperative for the design of clinical studies and that outcome may be enhanced by means of patient stratification strategies according to these hallmarks.Wed Mar 29 03:00:00 BST 2017MSV00008073428071820