Expression of the hedgehog signalling pathway and the effect of inhibition at the level of smoothened in canine osteosarcoma cell lines.
canine
cyclopamine
hedgehog signalling pathway
osteosarcoma
smoothened
Journal
Veterinary and comparative oncology
ISSN: 1476-5829
Titre abrégé: Vet Comp Oncol
Pays: England
ID NLM: 101185242
Informations de publication
Date de publication:
Dec 2022
Dec 2022
Historique:
revised:
12
04
2022
received:
04
02
2022
accepted:
03
05
2022
pubmed:
7
5
2022
medline:
15
11
2022
entrez:
6
5
2022
Statut:
ppublish
Résumé
Osteosarcoma (OSA) is the most common malignant bone cancer in dogs. Canine and human OSA share several features, including tumour environments, response to traditional treatment, and several molecular pathways. Hedgehog (Hh) signalling is known to contribute to tumorigenesis and progression of various cancers, including human OSA. This study aimed to identify the role of the Hh signalling pathway in canine OSA cell lines, including Abrams, D17, and Moresco, focusing on the signal transducer Smoothened (SMO). mRNA and protein levels of Hh pathway components, including SHH, IHH, SMO, and PTCH1, were aberrant in all examined OSA cell lines compared with canine osteoblast cells. The SMO inhibitor cyclopamine significantly decreased cell viability and colony-forming ability in the canine OSA cell lines in a dose-dependent manner. Moresco cells, which expressed the highest level of SMO protein, were the most sensitive to the anticancer effect of cyclopamine among the three canine OSA cell lines tested. Hh downstream target gene and protein expression in canine OSA cell lines were downregulated after cyclopamine treatment. In addition, cyclopamine significantly increased apoptotic cell death in Abrams and Moresco cells. The findings that Hh/SMO is activated in canine OSA cell lines and cyclopamine suppresses OSA cell survival via inhibition of SMO suggest that the Hh/SMO signalling pathway might be a novel therapeutic target for canine OSA.
Substances chimiques
Hedgehog Proteins
0
Receptors, G-Protein-Coupled
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
778-787Subventions
Organisme : Research Institute for Veterinary Science and BK21 Plus Program for Creative Veterinary Science Research, Seoul National University
Organisme : Seoul National University
ID : BK21
Informations de copyright
© 2022 John Wiley & Sons Ltd.
Références
Fenger JM, London CA, Kisseberth WC. Canine osteosarcoma: a naturally occurring disease to inform pediatric oncology. ILAR J. 2014;55(1):69-85.
Spodnick GJ, Berg J, Rand WM, et al. Prognosis for dogs with appendicular osteosarcoma treated by amputation alone: 162 cases (1978-1988). J Am Vet Med Assoc. 1992;200(7):995-999.
Berg J. Canine osteosarcoma: amputation and chemotherapy. Vet Clin North Am Small Anim Pract. 1996;26(1):111-121.
Thompson KG, Pool RR. Tumors of bones. In: Meuten DJ, ed. Tumors in Domestic Animals. 4th ed. Iowa State Press; 2002:245-318.
Szewczyk M, Lechowski R, Zabielska K. What do we know about canine osteosarcoma treatment? - review. Vet Res Commun. 2015;39(1):61-67.
Hirotsu M, Setoguchi T, Sasaki H, et al. Smoothened as a new therapeutic target for human osteosarcoma. Mol Cancer. 2010;9(1):5.
Lo WW, Pinnaduwage D, Gokgoz N, Wunder JS, Andrulis IL. Aberrant hedgehog signaling and clinical outcome in osteosarcoma. Sarcoma. 2014;2014:261804.
Dahmane N, Ruiz i Altaba A. Sonic hedgehog regulates the growth and patterning of the cerebellum. Development. 1999;126(14):3089-3100.
Varjosalo M, Taipale J. Hedgehog: functions and mechanisms. Genes Dev. 2008;22(18):2454-2472.
Rahnama F, Shimokawa T, Lauth M, et al. Inhibition of GLI1 gene activation by Patched1. Biochem J. 2006;394(Pt 1):19-26.
Rimkus TK, Carpenter RL, Qasem S, Chan M, Lo H-W. Targeting the sonic hedgehog signaling pathway: review of smoothened and GLI inhibitors. Cancer. 2016;8(2):22.
Taipale J, Chen JK, Cooper MK, et al. Effects of oncogenic mutations in smoothened and patched can be reversed by cyclopamine. Nature. 2000;406(6799):1005-1009.
Karhadkar SS, Bova GS, Abdallah N, et al. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature. 2004;431(7009):707-712.
Varnat F, Duquet A, Malerba M, et al. Human colon cancer epithelial cells harbour active HEDGEHOG-GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansion. EMBO Mol Med. 2009;1:338-351.
Feldmann G, Dhara S, Fendrich V, et al. Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res. 2007;67(5):2187-2196.
Stecca B, Mas C, Clement V, et al. Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways. Proc Natl Acad Sci U S A. 2007;104(14):5895-5900.
Shahi MH, Holt R, Rebhun RB. Blocking signaling at the level of GLI regulates downstream gene expression and inhibits proliferation of canine osteosarcoma cells. PLoS One. 2014;9(5):e96593.
Gustafson TL, Kitchell BE, Biller B. Hedgehog signaling is activated in canine transitional cell carcinoma and contributes to cell proliferation and survival. Vet Comp Oncol. 2017;15(1):174-183.
Baldanza VE, Rogic A, Yan W, et al. Evaluation of canonical hedgehog signaling pathway inhibition in canine osteosarcoma. PLoS One. 2020;15(4):e0231762.
Legare ME, Bush J, Ashley AK, Kato T, Hanneman WH. Cellular and phenotypic characterization of canine osteosarcoma cell lines. J Cancer. 2011;2:262-270.
Seo KW, Holt R, Jung YS, et al. Fluoroquinolone-mediated inhibition of cell growth, S-G2/M cell cycle arrest, and apoptosis in canine osteosarcoma cell lines. PLoS One. 2012;7(8):e42960.
O'Donoghue LE, Ptitsyn AA, Kamstock DA, Siebert J, Thomas RS, Duval DL. Expression profiling in canine osteosarcoma: identification of biomarkers and pathways associated with outcome. BMC Cancer. 2010;10(1):1-16.
Wilson-Robles HM, Daly M, Pfent C, Sheppard S. Identification and evaluation of putative tumour-initiating cells in canine malignant melanoma cell lines. Vet Comp Oncol. 2015;13(1):60-69.
Nam A, Kim T, Li Q, et al. Melarsomine suppresses canine osteosarcoma cell survival via inhibition of hedgehog-GLI signaling. J Vet Med Sci. 2019;81(12):1722-1729.
Hahn H, Wicking C, Zaphiropoulos PG, et al. Mutations of the human homolog of drosophila patched in the nevoid basal cell carcinoma syndrome. Cell. 1996;85(6):841-851.
Taipale J, Beachy PA. The hedgehog and Wnt signalling pathways in cancer. Nature. 2001;411(6835):349-354.
Thievessen I, Wolter M, Prior A, Seifert HH, Schulz WA. Hedgehog signaling in normal urothelial cells and in urothelial carcinoma cell lines. J Cell Physiol. 2005;203(2):372-377.
Lo W, Wunder J, Gokgoz N, Parkes R, Alman B, Andrulis I. Indian hedgehog signaling in osteosarcoma: co-expression of GLI1, PTCH1, and IHH. Cancer Res. 2007;67(9):1010.
Guo Y, Xiao P, Lei S, et al. How is mRNA expression predictive for protein expression? A correlation study on human circulating monocytes. Acta Biochim Biophys Sin (Shanghai). 2008;40(5):426-436.
Liu Y, Beyer A, Aebersold R. On the dependency of cellular protein levels on mRNA abundance. Cell. 2016;165(3):535-550.
Schwanhausser B, Busse D, Li N, et al. Global quantification of mammalian gene expression control. Nature. 2011;473(7347):337-342.
Baldi P, Long AD. A Bayesian framework for the analysis of microarray expression data: regularized t -test and statistical inferences of gene changes. Bioinformatics. 2001;17:509-519.
Szallasi Z. Genetic network analysis in light of massively parallel biological data acquisition. Pac Symp Biocomput. 1999;4:5-16.
Mao L, Xia YP, Zhou YN, et al. A critical role of sonic hedgehog signaling in maintaining the tumorigenicity of neuroblastoma cells. Cancer Sci. 2009;100(10):1848-1855.
Regl G, Kasper M, Schnidar H, et al. Activation of the BCL2 promoter in response to hedgehog/GLI signal transduction is predominantly mediated by GLI2. Cancer Res. 2004;64(21):7724-7731.
Chen XL, Cheng QY, She MR, et al. Expression of sonic hedgehog signaling components in hepatocellular carcinoma and cyclopamine-induced apoptosis through Bcl-2 downregulation in vitro. Arch Med Res. 2010;41(5):315-323.
Song M, Ou X, Xiao C, Xiao Z, Wei F, Hong Y. Hedgehog signaling inhibitor cyclopamine induces apoptosis by decreasing Gli2 and Bcl2 expression in human salivary pleomorphic adenoma cells. Biomed Rep. 2013;1(2):325-329.
Kiesslich T, Mayr C, Wachter J, et al. Activated hedgehog pathway is a potential target for pharmacological intervention in biliary tract cancer. Mol Cell Biochem. 2014;396(1-2):257-268.
Krawczyk N, Hartkopf A, Banys M, et al. Prognostic relevance of induced and spontaneous apoptosis of disseminated tumor cells in primary breast cancer patients. BMC Cancer. 2014;14:394.
Paoli P, Giannoni E, Chiarugi P. Anoikis molecular pathways and its role in cancer progression. Biochim Biophys Acta. 2013;1833(12):3481-3498.
Curran T. Reproducibility of academic preclinical translational research: lessons from the development of hedgehog pathway inhibitors to treat cancer. Open Biol. 2018;8(8):180098.
Tremblay MR, Lescarbeau A, Grogan MJ, et al. Discovery of a potent and orally active hedgehog pathway antagonist (IPI-926). J Med Chem. 2009;52(14):4400-4418.
Warzecha J, Dinges D, Kaszap B, Henrich D, Marzi I, Seebach C. Effect of the hedgehog-inhibitor cyclopamine on mice with osteosarcoma pulmonary metastases. Int J Mol Med. 2012;29(3):423-427.
Bernardini G, Geminiani M, Gambassi S, et al. Novel smoothened antagonists as anti-neoplastic agents for the treatment of osteosarcoma. J Cell Physiol. 2018;233(6):4961-4971.