title: RANK-Fc inhibits malignancy via inhibiting ERK activation and evoking caspase-3-mediated anoikis in human osteosarcoma cells.
abstract: Osteosarcoma (OS) is the most common primary malignant bone tumour, mainly afflicting the young. While there has been substantial improvement in treatment of OS with surgery and chemotherapy in the past two decades, this disease remains a significant health problem, warranting efforts to find better therapeutic options. In this study, we examined the RANK/RANKL axis in OS cells, using a RANK-Fc protein to perturb this coupling in an effort to reduce OS cell growth. RANK-Fc suppressed OS cell migration (P < 0.005), invasion ability (P < 0.05), and anchorage-independent ability in collagen-1 gel (P < 0.005) following induction of anoikis and activation of caspase-3. OS cell proliferation was not perturbed by RANK-Fc. The anti-invasion and anti-metastasis capability of RANK-Fc is attributed to reduced extracellular signal-regulated protein kinase (ERK) signaling via RANK-Fc, though activation of NFkappaB, and altered expression of Akt, p38, JNK, and matrix metalloproteinase (MMP)-2 and -9 were ruled out. In vivo, activity of the RANK-Fc against OS cell migration and invasion was confirmed in a model strictly monitoring metastasis. Thus, RANK-Fc, given its ability to directly reduce OS aggression, is a potential drug candidate.
authors.affiliation: Departments of Orthopaedics and Surgery, St. Vincent's Health, University of Melbourne,Fitzroy, Melbourne, VIC 3065, Australia.
authors.forename: Toru
authors.initials: T
authors.lastname: Akiyama
authors.forename: Peter F M
authors.initials: PF
authors.lastname: Choong
authors.forename: Crispin R
authors.initials: CR
authors.lastname: Dass
mesh_terms: D023102:Anoikis; D053148:Caspase 3 / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D012516:Osteosarcoma / Q000378:metabolism* / Q000473:pathology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: C517736:Rank-Fc; D011993:Recombinant Fusion Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3
references.citation: Nature. 2006 Mar 30;440(7084):692-6
references.pmid: 16572175
references.citation: Mol Cancer Res. 2008 Aug;6(8):1289-92
references.pmid: 18708361
references.citation: J Pathol. 2007 Apr;211(5):555-562
references.pmid: 17323424
references.citation: Nat Rev Cancer. 2006 Jun;6(6):449-58
references.pmid: 16723991
references.citation: J Immunol. 2007 Jul 1;179(1):266-74
references.pmid: 17579046
references.citation: Cancer Res. 2007 Nov 15;67(22):10744-52
references.pmid: 18006817
references.citation: Curr Opin Cell Biol. 2001 Oct;13(5):555-62
references.pmid: 11544023
references.citation: Bone. 2003 Nov;33(5):760-70
references.pmid: 14623051
references.citation: Nat Genet. 2000 Jan;24(1):45-8
references.pmid: 10615125
references.citation: Cancer Res. 2007 Aug 1;67(15):7308-18
references.pmid: 17671200
references.citation: J Biol Chem. 1998 Jun 5;273(23):14363-7
references.pmid: 9603945
references.citation: Cancer Biol Ther. 2009 Jan;8(2):106-17
references.pmid: 19098456
references.citation: J Exp Clin Cancer Res. 2009 Jul 22;28:105
references.pmid: 19624845
references.citation: Clin Exp Metastasis. 2007;24(2):93-106
references.pmid: 17458711
references.citation: Biochem Biophys Res Commun. 2003 Oct 24;310(3):774-8
references.pmid: 14550270
references.citation: J Orthop Res. 2007 Dec;25(12):1671-80
references.pmid: 17600821
references.citation: Cancer Metastasis Rev. 2009 Jun;28(1-2):247-63
references.pmid: 19214708
references.citation: J Cancer Res Clin Oncol. 2008 Mar;134(3):281-97
references.pmid: 17965883
references.citation: Cancer Biol Ther. 2008 Aug;7(8):1262-70
references.pmid: 18487955
references.citation: Cell. 1998 Apr 17;93(2):165-76
references.pmid: 9568710
references.citation: Nature. 2007 Feb 22;445(7130):E19; discussion E19-20
references.pmid: 17314931
references.citation: Clin Exp Metastasis. 2006;23(7-8):367-80
references.pmid: 17187230
references.citation: Endocrinology. 1999 Oct;140(10):4451-8
references.pmid: 10499498
references.citation: J Bone Miner Res. 1994 Sep;9(9):1489-99
references.pmid: 7817834
references.citation: Calcif Tissue Int. 2001 Mar;68(3):151-5
references.pmid: 11351498
references.citation: Matrix Biol. 1999 Jun;18(3):239-51
references.pmid: 10429943
references.citation: Prostate. 2008 Jun 1;68(8):820-9
references.pmid: 18324676
references.citation: Clin Exp Metastasis. 2005;22(8):643-52
references.pmid: 16649073
references.citation: Mol Cancer Ther. 2007 Dec;6(12 Pt 1):3263-70
references.pmid: 18089720
references.citation: Nat Rev Cancer. 2002 Aug;2(8):584-93
references.pmid: 12154351
references.citation: Nat Med. 2003 Aug;9(8):1026-32
references.pmid: 12872165
references.citation: Biomaterials. 2009 Sep;30(27):4815-23
references.pmid: 19505719