title: PTHrP attenuates osteoblast cell death and apoptosis induced by a novel class of anti-cancer agents.
abstract: The effectiveness of chemotherapeutic agents often limits their use due to their negative effects on normal cells. Apoptosis regulatory protein (CARP)-1 functional mimetics (CFMs) belong to a novel class of compounds that possess anti-cancer properties with potential utility in breast and other cancers. In this study, we investigated the growth inhibitory action of CFM-4 and -5 in bone-forming osteoblasts and role of a skeletal regulator, parathyroid hormone (PTH)-related peptide (PTHrP), which is frequently associated with oncologic pathologies. MC3T3E1-clone4 (MC-4) or primary osteoblasts were treated with CFMs. Western blots were performed to determine specific protein expressions. MTT, TUNEL assay, ethidium bromide/acridine orange staining, and ApoAlert caspase profiling were used to investigate cell viability and apoptosis of osteoblasts. Immunofluorescence staining was performed to observe intracellular localization of CARP-1. Our studies revealed that CFM-4 and -5 suppressed growths of mature differentiated, but not proliferating, MC-4 cells and PTHrP attenuated this effect. Mechanistically, induction of CARP-1 protein by CFM-4 and -5 was partially decreased by PTHrP. While CARP-1 increased by CFM-4 or -5 correlated with activated caspase-3, PTHrP remarkably blocked caspase-3 activation. PTHrP also influenced translocation of CFM-induced CARP-1 from the nucleus to the cytoplasm. Our data identify a new function of PTHrP in maintaining osteoblast homeostasis in chemotherapy and define a role of CARP-1 in this process. The crosstalk of PTHrP and CFM-4 and -5 signaling highlights the importance of CFMs as potential anti-cancer therapeutics in breast and other cancers which adversely affect bone.
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, Wayne State University School of Medicine, 1107 Elliman Clinical Research Building, 421 East Canfield Avenue, Detroit, MI, 48201, USA.
authors.forename: Sahiti
authors.initials: S
authors.lastname: Chukkapalli
authors.affiliation: Department of Pathology, Wayne State University School of Medicine, Detroit, MI, 48201, USA.|VA Medical Center, Detroit, MI, 48201, USA.
authors.forename: Edi
authors.initials: E
authors.lastname: Levi
authors.affiliation: Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA.|VA Medical Center, Detroit, MI, 48201, USA.|Department of Oncology, Wayne State University School of Medicine, Detroit, MI, 48201, USA.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Rishi
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, Wayne State University School of Medicine, 1107 Elliman Clinical Research Building, 421 East Canfield Avenue, Detroit, MI, 48201, USA. ndatta@med.wayne.edu.|Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA. ndatta@med.wayne.edu.|Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA. ndatta@med.wayne.edu.
authors.forename: Nabanita S
authors.initials: NS
authors.lastname: Datta
mesh_terms: D016475:3T3 Cells; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000187:drug effects*; D044162:Parathyroid Hormone-Related Protein / Q000494:pharmacology*; D061251:Primary Cell Culture; D014178:Translocation, Genetic / Q000187:drug effects
chemical_list: D018931:Antineoplastic Agents, Hormonal; D051017:Apoptosis Regulatory Proteins; C540324:CCAR1 protein, mouse; D018797:Cell Cycle Proteins; D044162:Parathyroid Hormone-Related Protein; D053148:Caspase 3
keywords: Apoptosis; CARP-1 functional mimetics; Osteoblast; PTHrP