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; Chemoresistance; GLI1; Glioma; MRP1; Shh.
MeSH terms
-
Apoptosis
-
Blotting, Western
-
Cell Proliferation
-
Drug Resistance, Multiple
-
Drug Resistance, Neoplasm*
-
Gene Expression Regulation, Neoplastic / drug effects*
-
Glioma / drug therapy
-
Glioma / genetics
-
Glioma / metabolism*
-
Hedgehog Proteins / antagonists & inhibitors
-
Hedgehog Proteins / genetics
-
Hedgehog Proteins / metabolism*
-
Humans
-
Multidrug Resistance-Associated Proteins / genetics
-
Multidrug Resistance-Associated Proteins / metabolism
-
Polycomb Repressive Complex 1 / antagonists & inhibitors
-
Polycomb Repressive Complex 1 / genetics
-
Polycomb Repressive Complex 1 / metabolism*
-
Pyridines / pharmacology*
-
Pyrimidines / pharmacology*
-
RNA, Messenger / genetics
-
RNA, Small Interfering / genetics
-
Real-Time Polymerase Chain Reaction
-
Reverse Transcriptase Polymerase Chain Reaction
-
Signal Transduction
-
Tumor Cells, Cultured
-
Zinc Finger Protein GLI1 / antagonists & inhibitors
-
Zinc Finger Protein GLI1 / genetics
-
Zinc Finger Protein GLI1 / metabolism*
Substances
-
BMI1 protein, human
-
GANT 61
-
GLI1 protein, human
-
Hedgehog Proteins
-
Multidrug Resistance-Associated Proteins
-
Pyridines
-
Pyrimidines
-
RNA, Messenger
-
RNA, Small Interfering
-
SHH protein, human
-
Zinc Finger Protein GLI1
-
Polycomb Repressive Complex 1
-
multidrug resistance-associated protein 1