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Tumor Biology

, Volume 37, Issue 11, pp 15107–15114 | Cite as

Potential role of Shh-Gli1-BMI1 signaling pathway nexus in glioma chemoresistance

  • M. H. Shahi
  • S. Farheen
  • M. P. M. Mariyath
  • J. S. Castresana
Original Article

Abstract

Chemoresistance is a common hurdle for the proper treatment of gliomas. The role of Shh-Gli1 signaling in glioma progression has been reported. However, its role in glioma chemoresistance has not been well studied yet. In this work, we found that Shh-Gli1 signaling regulates the expression of one stem cell marker, BMI1 (B cell-specific Moloney murine leukemia virus), in glioma. Interestingly, we also demonstrated high expression of MRP1 (multi-drug resistance protein 1) in glioma. MRP1 expression was decreased by BMI1 siRNA and Shh-Gli1 cell signaling specific inhibitor GANT61 in our experiments. GANT61 very efficiently inhibited cell colony growth in glioma cell lines, compared to temozolomide. Moreover, a synergic effect of GANT61 and temozolomide drastically decreased the LD50 of temozolomide in the cell colony experiments. Therefore, our results suggest that there is a potential nexus of Shh-Gli1-BMI1 cell signaling to regulate MRP1 and to promote chemoresistance in glioma. Henceforth, our study opens the possibility of facing new targets, Gli1 and BMI1, for the effective treatment of glioma suppression of chemoresistance with adjuvant therapy of GANT61 and temozolomide.

Keywords

BMI1 MRP1 Shh Glioma Chemoresistance GLI1 

Abbreviations

ATCC

American Type Culture Collection

BTSC

Brain tumor stem cells

BMI 1

B cell-specific Moloney murine leukemia virus integration site 1

DMEM

Dulbecco’s modified Eagle’s medium

DMSO

Dimethyl sulfoxide

FBS

Fetal bovine serum

GANT-61

GLI1 antagonist

GFP

Green fluorescence protein

Gli1

Glioma-associated oncogene homologue 1

LD50

Lethal dose, 50 %

MRP-1

Multi-drug resistance-associated protein-1

MTS

Methyl tetrazole sulfate

PAGE

Poly acrylamide gel electrophoresis

PBS

Phosphate-buffered saline

PRC1

Polycomb-repressing complex 1

qRT-PCR

Quantitative real-time polymerase chain reaction

Shh

Sonic hedgehog

SiRNA

Small interference ribonucleic acid

SMO

Smoothened

TMZ

Temozolomide

UT

Untreated

Notes

Acknowledgments

The authors are grateful to the Department of Biotechnology, Government of India, for partially providing funds to accomplish this work. MHS thanks Dr. Rebhun, University of California, Davis, USA, for the support to perform these experiments. MHS is the Young Investigator in Cancer Biology from the Department of Biotechnology, Government of India, New Delhi.

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • M. H. Shahi
    • 1
  • S. Farheen
    • 1
  • M. P. M. Mariyath
    • 1
  • J. S. Castresana
    • 2
  1. 1.Interdisciplinary Brain Research Centre, Faculty of MedicineAligarh Muslim UniversityAligarhIndia
  2. 2.Department of Biochemistry and GeneticsUniversity of Navarra School of SciencesPamplonaSpain

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