title: All-trans retinoic acid inhibits tumor growth of human osteosarcoma             by activating Smad signaling-induced osteogenic differentiation.
abstract: Osteosarcoma (OS) is one of the most common malignant bone tumors. Despite             the advancement of diagnosis and treatment for OS, the prognosis remains poor.             We investigated the proliferation inhibitory effect of all-trans retinoic acid             (ATRA) for human OS and the possible mechanism underlying this effect. We examined             the proliferation inhibition and apoptosis-inducing effects of ATRA in 143B OS             cells. We validated this effect by exogenously expressing the retinoic acid receptor             alpha (RARα) in 143B OS cells and injecting the cells into nude mice. We explored             the possible mechanism for the proliferation inhibitory effect of ATRA on OS cells             and multipotential progenitor cells by detecting osteogenic markers. We demonstrated             that the endogenous retinoic acid receptor and retinoid X receptor are all detectable             in the commercially available OS cell lines and in primary osteosarcoma cells.             ATRA inhibits the proliferation of OS cells in a concentration-dependent manner,             as well as induces apoptosis in 143B OS cells. The exogenous expression of RARα             inhibits the tumor growth and cell proliferation in vivo. The alkaline phosphatase             activity, protein levels of osteopontin (OPN) and osteocalcin (OCN) are all promoted             by ATRA in OS cells and mouse embryonic fibroblasts (MEFs), at least by activating             the Smad signaling pathway. Collectively, our results strongly indicate that ATRA             can inhibit the tumor growth of OS by promoting osteogenic differentiation in             OS cells, which is mediated in part by activating Smad signaling. Therefore, combination             of ATRA with other current chemotherapy agents may be a promising therapy strategy             for OS treatment.
authors.affiliation: Key Laboratory of Diagnostic Medicine designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, PR China.
authors.forename: Qiu-Jun
authors.initials: QJ
authors.lastname: Yang
authors.forename: Long-Yang
authors.initials: LY
authors.lastname: Zhou
authors.forename: Yu-Qin
authors.initials: YQ
authors.lastname: Mu
authors.forename: Qi-Xin
authors.initials: QX
authors.lastname: Zhou
authors.forename: Jin-Yong
authors.initials: JY
authors.lastname: Luo
authors.forename: Lang
authors.initials: L
authors.lastname: Cheng
authors.forename: Zhong-Liang
authors.initials: ZL
authors.lastname: Deng
authors.forename: Tong-Chuan
authors.initials: TC
authors.lastname: He
authors.forename: Rex C
authors.initials: RC
authors.lastname: Haydon
authors.forename: Bai-Cheng
authors.initials: BC
authors.lastname: He
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D017930:Genes, Reporter; D006801:Humans; D049409:Luciferases, Firefly / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010012:Osteogenesis; D012516:Osteosarcoma / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D047490:Retinoid X Receptor alpha / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D000943:Antigens, Differentiation; D000970:Antineoplastic Agents; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047490:Retinoid X Receptor alpha; D051785:Smad Proteins; D014212:Tretinoin; D049409:Luciferases, Firefly; C505407:CASP3 protein, human; D053148:Caspase 3