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Temozolomide induces activation of Wnt/β-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy

  • Vivek Singh Tomar
  • Vikas Patil
  • Kumaravel SomasundaramEmail author
Short Communication

Abstract

Glioblastoma (GBM) is the most aggressive type of glioma. Temozolomide (TMZ) is currently the drug of choice used for post-operative chemotherapy of GBM. However, the presence of intrinsic and acquired resistance hinders the success of chemotherapy. To understand the TMZ resistant mechanisms in glioma, we investigated the alterations in cellular signaling pathways by performing transcriptome analysis of TMZ treated glioma cells. Gene Set Enrichment Analysis (GSEA) indicated a significant enrichment of Wnt/β-catenin signaling besides many other pathways in TMZ treated cells. Further, we demonstrate that TMZ treatment increased the activity from TOPflash reporter, (a Wnt responsive reporter), enhanced the levels of pGSK-3β (S9) and reduced the levels of p-β-catenin (S33/37/T41) with a concomitant increase in transcript and protein levels of Wnt targets in a concentration and time-dependent manner. While TMZ treated cells did not show alteration in any of the Wnt ligands, PI3K inhibitor (LY294002) treatment repressed Akt activation and abolished the TMZ–mediated induction of Wnt/β-catenin pathway. In addition, we show that Wnt/β-catenin signaling activation by TMZ is independent of ATM/Chk2 pathway. Further, we also demonstrate the activation of mTOR pathway after TMZ treatment. Thus, our results demonstrate that activation of Wnt/β-catenin pathway involves an ATM/Chk2- independent PI3K/Akt/GSK-3 cascade in TMZ treated cells and further provides mechanistic basis for the chemoresistance of glioma to TMZ.

Keywords

Glioblastoma Microarray Temozolomide Transcriptome Resistance 

Abbreviations

GBM

Glioblastoma

TMZ

Temozolomide

DAVID

Database for Annotation, Visualization and Integrated Discovery

GSEA

Gene Set Enrichment Analysis

MSigDB

Molecular signature database

Notes

Acknowledgments

We thank Dr. Subba Rao and Dr. Deepak Saini (I.I.Sc., Bangalore) for providing the shRNA constructs. We acknowledge use of GSEA software and MSigDB (Mootha et al. 2003; Subramanian et al. 2005).

Funding information

VS acknowledge IISc for the research fellowship. KS acknowledges CSIR, DST, SERB, CEFIPRA, and DBT, Government of India, for research grants. Infrastructure support by funding from DST-FIST and UGC (Center for Advanced Studies in Molecular Microbiology) to MCB and DBT-IISc partnership program is acknowledged. KS is a J. C. Bose Fellow of the Department of Science and Technology.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

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Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • Vivek Singh Tomar
    • 1
  • Vikas Patil
    • 1
  • Kumaravel Somasundaram
    • 1
    Email author
  1. 1.Department of Microbiology and Cell BiologyIndian Institute of ScienceBangaloreIndia

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