Premium
Suppression of STAT3 NH 2 ‐terminal domain chemosensitizes medulloblastoma cells by activation of protein inhibitor of activated STAT3 via de‐repression by microRNA‐21
Author(s) -
Ray Sutapa,
Coulter Don W.,
Gray Shawn D.,
Sughroue Jason A.,
Roychoudhury Shrabasti,
McIntyre Erin M.,
Chaturvedi Nagendra K.,
Bhakat Kishor K.,
Joshi Shantaram S.,
McGuire Timothy R.,
Sharp John G.
Publication year - 2018
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.22778
Subject(s) - biology , stat3 , cancer research , cyclin d1 , microrna , cell growth , wnt signaling pathway , signal transduction , apoptosis , microbiology and biotechnology , cell cycle , gene , genetics , biochemistry
Medulloblastoma (MB) is a malignant pediatric brain tumor with poor prognosis. Signal transducers and activators of transcription‐3 (STAT3) is constitutively activated in MB where it functions as an oncoprotein, mediating cancer progression and metastasis. Here, we have delineated the functional role of activated STAT3 in MB, by using a cell permeable STAT3‐NH 2 terminal domain inhibitor (S3‐NTDi) that specifically perturbs the structure/function of STAT3. We have implemented several biochemical experiments using human MB tumor microarray (TMA) and pediatric MB cell lines, derived from high‐risk SHH‐TP53‐mutated and MYC‐amplified Non‐WNT/SHH tumors. Treatment of MB cells with S3‐NTDi leads to growth inhibition, cell cycle arrest, and apoptosis. S3‐NTDi downregulated expression of STAT3 target genes, delayed migration of MB cells, attenuated epithelial‐mesenchymal transition (EMT) marker expressions and reduced cancer stem‐cell associated protein expressions in MB‐spheres. To elucidate mechanisms, we showed that S3‐NTDi induce expression of pro‐apoptotic gene, C/EBP‐homologous protein (CHOP), and decrease association of STAT3 to the proximal promoter of CCND1 and BCL2. Of note, S3‐NTDi downregulated microRNA‐21, which in turn, de‐repressed Protein Inhibitor of Activated STAT3 (PIAS3), a negative regulator of STAT3 signaling pathway. Furthermore, combination therapy with S3‐NTDi and cisplatin significantly decreased highly aggressive MYC‐amplified MB cell growth and induced apoptosis by downregulating STAT3 regulated proliferation and anti‐apoptotic gene expression. Together, our results revealed an important role of STAT3 in regulating MB pathogenesis. Disruption of this pathway with S3‐NTDi, therefore, may serves as a promising candidate for targeted MB therapy by enhancing chemosensitivity of MB cells and potentially improving outcomes in high‐risk patients.