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

  • Original Article
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Tumor Biology

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.

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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

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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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Authors and Affiliations

  1. Interdisciplinary Brain Research Centre, Faculty of Medicine, Aligarh Muslim University, Aligarh, UP, 202002, India

    M. H. Shahi, S. Farheen & M. P. M. Mariyath

  2. Department of Biochemistry and Genetics, University of Navarra School of Sciences, Irunlarrea 1, 31008, Pamplona, Spain

    J. S. Castresana

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  1. M. H. Shahi
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  2. S. Farheen
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  3. M. P. M. Mariyath
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Correspondence to M. H. Shahi.

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Shahi, M.H., Farheen, S., Mariyath, M.P.M. et al. Potential role of Shh-Gli1-BMI1 signaling pathway nexus in glioma chemoresistance. Tumor Biol. 37, 15107–15114 (2016). https://doi.org/10.1007/s13277-016-5365-7

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  • DOI: https://doi.org/10.1007/s13277-016-5365-7

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