Coleusin factor, a novel anticancer diterpenoid, inhibits osteosarcoma growth by inducing bone morphogenetic protein-2-dependent differentiation.
Coleusin factor is a diterpenoid compound isolated from the root of a tropical plant, Coleus forskohlii. Although Coleusin factor has been reported to suppress proliferation of and induce apoptosis in several types of cancer cells, the effects of Coleusin factor on osteosarcoma and the underlying mechanism are still not fully understood. In this study, we show that Coleusin factor treatment potently inhibits the growth of osteosarcoma cells associated with G(1) cell-cycle arrest. Interestingly, apoptosis and cell death are not induced. Instead, Coleusin factor causes osteosarcoma cells to exhibit typical properties of differentiated osteoblasts, including a morphologic alteration resembling osteoblasts, the expression of osteoblast differentiation markers, elevated alkaline phosphatase activity, and increased cellular mineralization. Coleusin factor treatment significantly increases the expression of bone morphogenetic protein-2 (BMP-2), a crucial osteogenic regulator, and runt-related transcription factor 2 (RUNX2), one of the key transcription factors of the BMP pathway. When BMP-2 signaling is blocked, Coleusin factor fails to inhibit cell proliferation and to induce osteoblast differentiation. Thus, upregulation of BMP-2 autocrine is critical for Coleusin factor to induce osteoblast differentiation and exert its anticancer effects on osteosarcoma. Importantly, administration of Coleusin factor inhibits the growth of osteosarcoma xenografted in nude mice without systemic or immunologic toxicity. Osteosarcoma is a highly aggressive cancer marked by the loss of normal differentiation. Coleusin factor represents a new type of BMP-2 inducer that restores differentiation in osteosarcoma cells. It may provide a promising therapeutic strategy against osteosarcoma with minimal side effects.
Authors' Affiliations: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Graduate University of Chinese Academy of Sciences; Department of Biology, Capital Normal University, Beijing, China; and Department of Biological Sciences, Virginia Tech, Blacksburg, VirginiaAuthors' Affiliations: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Graduate University of Chinese Academy of Sciences; Department of Biology, Capital Normal University, Beijing, China; and Department of Biological Sciences, Virginia Tech, Blacksburg, VirginiaAuthors' Affiliations: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Graduate University of Chinese Academy of Sciences; Department of Biology, Capital Normal University, Beijing, China; and Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia.
Shuo
S
Geng
Authors' Affiliations: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Graduate University of Chinese Academy of Sciences; Department of Biology, Capital Normal University, Beijing, China; and Department of Biological Sciences, Virginia Tech, Blacksburg, VirginiaAuthors' Affiliations: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Graduate University of Chinese Academy of Sciences; Department of Biology, Capital Normal University, Beijing, China; and Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia.
Bo
B
Sun
Authors' Affiliations: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Graduate University of Chinese Academy of Sciences; Department of Biology, Capital Normal University, Beijing, China; and Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia.
Ran
R
Lu
Authors' Affiliations: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Graduate University of Chinese Academy of Sciences; Department of Biology, Capital Normal University, Beijing, China; and Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia jzwang.ioz@gmail.com.
Jingze
J
Wang
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D055396:Bone Morphogenetic Protein 2 / Q000096:biosynthesis* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D050659:Core Binding Factor Alpha 1 Subunit / Q000096:biosynthesis; D004224:Diterpenes / Q000008:administration & dosage*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D012516:Osteosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D050659:Core Binding Factor Alpha 1 Subunit; D004224:Diterpenes; C493709:RUNX2 protein, human; C000595236:coleusin factor