title: miR-138 overexpression is more powerful than hTERT knockdown to potentiate apigenin for apoptosis in neuroblastoma in vitro and in vivo.
abstract: Decrease in expression of the tumor suppressor microRNA-138 (miR-138) correlates well with an increase in telomerase activity in many human cancers. The ability of almost all human cancer cells to grow indefinitely is dependent on presence of telomerase activity. The catalytic component of human telomerase reverse transcriptase (hTERT) regulates telomerase activity in most of the human cancers including malignant neuroblastoma. We observed an indirect increase in the expression of miR-138 after the transfection with hTERT short hairpin RNA (shRNA) plasmid in human malignant neuroblastoma SK-N-DZ and SK-N-BE2 cell lines. Transfection with hTERT shRNA plasmid followed by treatment with the flavonoid apigenin (APG) further increased expression of miR-138. Direct transfection with miR-138 mimic was more powerful than transfection with hTERT shRNA plasmid in potentiating efficacy of APG for decreasing cell viability and colony formation capability of both cell lines. Upregulation of miR-138 was also more effective than down regulation of hTERT in enhancing efficacy of APG for induction of apoptosis in malignant neuroblastoma cells in vitro and in vivo. We delineated that apoptosis occurred with induction of molecular components of the extrinsic and intrinsic pathways in SK-N-DZ and SK-N-BE2 cells both in vitro and in vivo. In conclusion, these results demonstrate that direct miR-138 overexpression is more powerful than hTERT down regulation in enhancing pro-apoptotic effect of APG for controlling growth of human malignant neuroblastoma in cell culture and animal models.
authors.affiliation: Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC, USA.
authors.forename: Mrinmay
authors.initials: M
authors.lastname: Chakrabarti
authors.forename: Naren L
authors.initials: NL
authors.lastname: Banik
authors.forename: Swapan K
authors.initials: SK
authors.lastname: Ray
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D047310:Apigenin / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques / Q000379:methods*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism; D010957:Plasmids / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
chemical_list: D017304:Annexin A5; D000972:Antineoplastic Agents, Phytogenic; C546110:MIRN138 microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; D047310:Apigenin; C509186:TERT protein, human; D019098:Telomerase
references.citation: Brain Res. 2012 May 15;1454:1-13
references.pmid: 22498172
references.citation: Leuk Res. 2010 Aug;34(8):1078-82
references.pmid: 19896708
references.citation: Nucleic Acids Res. 2004 Jan 1;32(Database issue):D109-11
references.pmid: 14681370
references.citation: Oncogene. 2006 Aug 7;25(34):4798-811
references.pmid: 16892092
references.citation: Int J Cancer. 1998 Nov 23;78(5):539-43
references.pmid: 9808519
references.citation: Cancer Sci. 2008 Feb;99(2):280-6
references.pmid: 18201269
references.citation: Cancer Metastasis Rev. 2009 Dec;28(3-4):369-78
references.pmid: 20012925
references.citation: RNA Biol. 2009 Jul-Aug;6(3):335-40
references.pmid: 19535911
references.citation: J Cell Mol Med. 2009 Oct;13(10):4205-18
references.pmid: 19473291
references.citation: Exp Mol Med. 2001 Sep 30;33(3):156-63
references.pmid: 11642552
references.citation: Neurosci Lett. 2006 Oct 16;407(1):53-8
references.pmid: 16949208
references.citation: Int J Cancer. 1999 Aug 20;84(4):426-31
references.pmid: 10404098
references.citation: Am J Pathol. 1998 Sep;153(3):857-64
references.pmid: 9736034
references.citation: Exp Cell Res. 2012 Aug 1;318(13):1597-610
references.pmid: 22507272
references.citation: Gene Ther. 2007 May;14(10):790-803
references.pmid: 17344905
references.citation: Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):12085-90
references.pmid: 19597153
references.citation: Neurochem Res. 2009 Jan;34(1):66-78
references.pmid: 18357521
references.citation: Nat Protoc. 2006;1(5):2315-9
references.pmid: 17406473
references.citation: Clin Cancer Res. 2009 Dec 1;15(23):7186-95
references.pmid: 19934306
references.citation: Pediatr Nephrol. 2009 Nov;24(11):2137-46
references.pmid: 18320238
references.citation: J Biol Chem. 1999 May 7;274(19):13085-90
references.pmid: 10224060
references.citation: Cancer Res. 2010 Sep 15;70(18):7027-30
references.pmid: 20807816
references.citation: Biochem J. 2011 Nov 15;440(1):23-31
references.pmid: 21770894
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: Oncogene. 2008 Dec;27 Suppl 2:S52-7
references.pmid: 19956180
references.citation: Biochem Biophys Res Commun. 2009 Oct 30;388(4):705-10
references.pmid: 19695221
references.citation: Oncogene. 2002 Jan 21;21(4):541-52
references.pmid: 11850779
references.citation: Int J Oncol. 2002 Sep;21(3):493-7
references.pmid: 12168091
references.citation: Neurochem Res. 2011 Dec;36(12):2292-305
references.pmid: 21786169
references.citation: Neurochem Res. 2013 Feb;38(2):420-32
references.pmid: 23192662
references.citation: Nucleic Acids Res. 2005 Sep 28;33(17):5394-403
references.pmid: 16192569