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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.
AuthorsMrinmay Chakrabarti, Naren L Banik, Swapan K Ray
JournalExperimental cell research (Exp Cell Res) Vol. 319 Issue 10 Pg. 1575-85 (Jun 10 2013) ISSN: 1090-2422 [Electronic] United States
PMID23562653 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2013 Elsevier Inc. All rights reserved.
Chemical References
  • Annexin A5
  • Antineoplastic Agents, Phytogenic
  • MIRN138 microRNA, human
  • MicroRNAs
  • RNA, Small Interfering
  • Apigenin
  • TERT protein, human
  • Telomerase
Topics
  • Animals
  • Annexin A5 (metabolism)
  • Antineoplastic Agents, Phytogenic (pharmacology)
  • Apigenin (pharmacology)
  • Apoptosis
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Drug Synergism
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques (methods)
  • Humans
  • Mice
  • Mice, Nude
  • MicroRNAs (genetics, metabolism)
  • Neuroblastoma (genetics, metabolism)
  • Plasmids (genetics, metabolism)
  • RNA, Small Interfering (genetics, metabolism)
  • Telomerase (genetics, metabolism)
  • Transfection
  • Tumor Stem Cell Assay
  • Xenograft Model Antitumor Assays

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