BCL3 expression promotes resistance to alkylating chemotherapy in gliomas.
Longtao WuGiovanna M BernalKirk E CahillPeter PytelCarrie A FitzpatrickHeather MashekRalph R WeichselbaumBakhtiar YaminiPublished in: Science translational medicine (2019)
The response of patients with gliomas to alkylating chemotherapy is heterogeneous. However, there are currently no universally accepted predictors of patient response to these agents. We identify the nuclear factor κB (NF-κB) co-regulator B cell CLL/lymphoma 3 (BCL-3) as an independent predictor of response to temozolomide (TMZ) treatment. In glioma patients with tumors that have a methylated O6-methylguanine DNA methyltransferase (MGMT) promoter, high BCL-3 expression was associated with a poor response to TMZ. Mechanistically, BCL-3 promoted a more malignant phenotype by inducing an epithelial-to-mesenchymal transition in glioblastomas through promoter-specific NF-κB dimer exchange. Carbonic anhydrase II (CAII) was identified as a downstream factor promoting BCL-3-mediated resistance to chemotherapy. Experiments in glioma xenograft mouse models demonstrated that the CAII inhibitor acetazolamide enhanced survival of TMZ-treated animals. Our data suggest that BCL-3 might be a useful indicator of glioma response to alkylating chemotherapy and that acetazolamide might be repurposed as a chemosensitizer for treating TMZ-resistant gliomas.
Keyphrases
- nuclear factor
- high grade
- locally advanced
- poor prognosis
- transcription factor
- signaling pathway
- dna methylation
- gene expression
- oxidative stress
- lps induced
- mouse model
- pi k akt
- squamous cell carcinoma
- electronic health record
- long non coding rna
- diffuse large b cell lymphoma
- rectal cancer
- case report
- newly diagnosed
- big data
- single molecule
- machine learning
- cell proliferation
- circulating tumor
- free survival
- data analysis