Arsenic trioxide induces autophagy and apoptosis in human glioma cells in vitro and in vivo through downregulation of survivin

Hui Wen Chiu, Yuan Soon Ho, Ying Jan Wang

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49 Citations (Scopus)

Abstract

Gliomas are the most aggressive of all human malignancies. Survivin is overexpressed in gliomas, and overexpression of survivin is associated with the progression of gliomas and the poor prognosis of glioma patients. Arsenic trioxide (ATO) is used in patients with acute promyelocytic leukemia and is active in vitro in several solid tumor cell lines. In the present study, the human glioma cell line U118-MG was used to investigate the anti-cancer effect of ATO in vitro and in vivo. The molecular mechanisms of the relationship between cell death (autophagy and apoptosis) and survivin were analyzed. ATO reduced cell viability through an increase in mitotic cells in a concentration-dependent manner. The mechanisms of ATO-induced autophagy and apoptosis were mediated by the inhibition of PI3K/Akt and the activation of MAPK signaling pathways. The ATO treatment of U118-MG cells pre-treated with specific chemical inhibitors of PI3K/AKT and MAPK significantly changed the cytotoxicity and the expression of survivin, suggesting that survivin plays a pivotal role in ATO-induced cell death. When U118-MG cells were transfected with survivin shRNA, the results demonstrated a significant increase in apoptotic and autophagic cells. In in vivo studies, the ATO treatment of SCID mice showed a significant tumor growth delay time and the decreased expression of survivin in tumor tissue. An important result from the current study is the finding that survivin could suppress both autophagy and apoptosis in glioma cells. This study suggests that ATO treatment or survivin inhibition could be a novel therapeutic strategy in malignant gliomas.

Original languageEnglish
Pages (from-to)927-941
Number of pages15
JournalJournal of Molecular Medicine
Volume89
Issue number9
DOIs
Publication statusPublished - Sep 2011
Externally publishedYes

Fingerprint

Autophagy
Glioma
Down-Regulation
Apoptosis
Phosphatidylinositol 3-Kinases
Neoplasms
Cell Death
Acute Promyelocytic Leukemia
SCID Mice
In Vitro Techniques
arsenic trioxide
Therapeutics
Tumor Cell Line
Small Interfering RNA
Cell Survival
Cell Line
Growth

Keywords

  • Apoptosis
  • Arsenic trioxide
  • Autophagy
  • Cancer
  • Cell cycle
  • Cell death
  • Glioma
  • Survivin

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

Cite this

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title = "Arsenic trioxide induces autophagy and apoptosis in human glioma cells in vitro and in vivo through downregulation of survivin",
abstract = "Gliomas are the most aggressive of all human malignancies. Survivin is overexpressed in gliomas, and overexpression of survivin is associated with the progression of gliomas and the poor prognosis of glioma patients. Arsenic trioxide (ATO) is used in patients with acute promyelocytic leukemia and is active in vitro in several solid tumor cell lines. In the present study, the human glioma cell line U118-MG was used to investigate the anti-cancer effect of ATO in vitro and in vivo. The molecular mechanisms of the relationship between cell death (autophagy and apoptosis) and survivin were analyzed. ATO reduced cell viability through an increase in mitotic cells in a concentration-dependent manner. The mechanisms of ATO-induced autophagy and apoptosis were mediated by the inhibition of PI3K/Akt and the activation of MAPK signaling pathways. The ATO treatment of U118-MG cells pre-treated with specific chemical inhibitors of PI3K/AKT and MAPK significantly changed the cytotoxicity and the expression of survivin, suggesting that survivin plays a pivotal role in ATO-induced cell death. When U118-MG cells were transfected with survivin shRNA, the results demonstrated a significant increase in apoptotic and autophagic cells. In in vivo studies, the ATO treatment of SCID mice showed a significant tumor growth delay time and the decreased expression of survivin in tumor tissue. An important result from the current study is the finding that survivin could suppress both autophagy and apoptosis in glioma cells. This study suggests that ATO treatment or survivin inhibition could be a novel therapeutic strategy in malignant gliomas.",
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AU - Ho, Yuan Soon

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N2 - Gliomas are the most aggressive of all human malignancies. Survivin is overexpressed in gliomas, and overexpression of survivin is associated with the progression of gliomas and the poor prognosis of glioma patients. Arsenic trioxide (ATO) is used in patients with acute promyelocytic leukemia and is active in vitro in several solid tumor cell lines. In the present study, the human glioma cell line U118-MG was used to investigate the anti-cancer effect of ATO in vitro and in vivo. The molecular mechanisms of the relationship between cell death (autophagy and apoptosis) and survivin were analyzed. ATO reduced cell viability through an increase in mitotic cells in a concentration-dependent manner. The mechanisms of ATO-induced autophagy and apoptosis were mediated by the inhibition of PI3K/Akt and the activation of MAPK signaling pathways. The ATO treatment of U118-MG cells pre-treated with specific chemical inhibitors of PI3K/AKT and MAPK significantly changed the cytotoxicity and the expression of survivin, suggesting that survivin plays a pivotal role in ATO-induced cell death. When U118-MG cells were transfected with survivin shRNA, the results demonstrated a significant increase in apoptotic and autophagic cells. In in vivo studies, the ATO treatment of SCID mice showed a significant tumor growth delay time and the decreased expression of survivin in tumor tissue. An important result from the current study is the finding that survivin could suppress both autophagy and apoptosis in glioma cells. This study suggests that ATO treatment or survivin inhibition could be a novel therapeutic strategy in malignant gliomas.

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