Gli1 is a potential target for alleviating multidrug resistance of gliomas

J Neurol Sci. 2010 Jan 15;288(1-2):156-66. doi: 10.1016/j.jns.2009.09.006. Epub 2009 Oct 12.

Abstract

Although chemotherapy plays an important role in combined treatment of human gliomas, it fails to bring about satisfactory outcomes in a number of patients. One of the major obstacles in this treatment is the development of multidrug resistance (MDR) during treatment. Regulation of MDR in the context of gliomas is poorly understood, and clinical efforts to inhibit it have not been fruitful. Activation of the Hedgehog (HH) pathway has been shown to contribute to the growth, maintenance and relapse of various cancers. As data were not available on the role of Gli1 expression in glioma progression, we analyzed the correlation between Gli1 expression and tumor recurrence after chemotherapy in 60 glioma samples. The effects of inhibiting or activating the HH pathway on sensitizing or rendering glioma cell lines resistant to VCR, VP16, CDDP and ACNU, which are widely used in clinical chemotherapy, were determined. Additionally, the impact of the HH pathway on the expressions of MDR1, MRP1, MVP, MGMT, Bcl-2 and Survivin genes was determined. Our results indicate that overexpression of Gli1 is correlated with glioma recurrence after chemotherapy. We further show that the HH pathway activity can promote clonogenic survival of glioma cell lines in chemotherapy. Additionally, we found that blocking the HH pathway enhanced cytotoxicity of chemotherapeutic agents in glioma cells, through down-regulating the expressions of MDR1, MRP1, MVP, MGMT, Bcl-2 and Survivin genes. Taken together, these results suggest that Gli1 plays a dominant role in chemoresistance of glioma cells, and that suppression of Gli1 expression might be a valid therapeutic option for overcoming MDR and for increasing the success of chemotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / therapeutic use*
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Blotting, Western
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / genetics*
  • Cell Line, Tumor
  • DNA, Complementary / biosynthesis
  • DNA, Complementary / genetics
  • Drug Resistance, Multiple / genetics*
  • Drug Resistance, Neoplasm / genetics*
  • Glioma / drug therapy*
  • Glioma / genetics*
  • Humans
  • Immunohistochemistry
  • Indicators and Reagents
  • Lentivirus / genetics
  • Neoplasm Recurrence, Local / genetics
  • RNA, Neoplasm / biosynthesis
  • RNA, Neoplasm / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Tetrazolium Salts
  • Transcription Factors / drug effects*
  • Transcription Factors / genetics*
  • Transfection
  • Tumor Stem Cell Assay
  • Zinc Finger Protein GLI1

Substances

  • Antineoplastic Agents
  • DNA, Complementary
  • GLI1 protein, human
  • Indicators and Reagents
  • RNA, Neoplasm
  • Tetrazolium Salts
  • Transcription Factors
  • Zinc Finger Protein GLI1
  • 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-((phenylamino)carbonyl)-2H-tetrazolium hydroxide