Research Papers:
Different BCR/Abl protein suppression patterns as a converging trait of chronic myeloid leukemia cell adaptation to energy restriction
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Abstract
Silvia Bono1, Matteo Lulli1, Vito Giuseppe D’Agostino2, Federico Di Gesualdo1, Rosa Loffredo2, Maria Grazia Cipolleschi1, Alessandro Provenzani2, Elisabetta Rovida1, Persio Dello Sbarba1
1Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, Università degli Studi di Firenze, Florence, Italy
2Centre For Integrative Biology (CIBIO), Università degli Studi di Trento, Trento, Italy
Correspondence to:
Persio Dello Sbarba, email: [email protected]
Matteo Lulli, email: [email protected]
Elisabetta Rovida, email: [email protected]
Keywords: transcriptional regulation, translational regulation, post-translational regulation, hypoxia, glucose shortage
Received: August 11, 2016 Accepted: October 28, 2016 Published: November 12, 2016
ABSTRACT
BCR/Abl protein drives the onset and progression of Chronic Myeloid Leukemia (CML). We previously showed that BCR/Abl protein is suppressed in low oxygen, where viable cells retain stem cell potential. This study addressed the regulation of BCR/Abl protein expression under oxygen or glucose shortage, characteristic of the in vivo environment where cells resistant to tyrosine kinase inhibitors (TKi) persist. We investigated, at transcriptional, translational and post-translational level, the mechanisms involved in BCR/Abl suppression in K562 and KCL22 CML cells. BCR/abl mRNA steady-state analysis and ChIP-qPCR on BCR promoter revealed that BCR/abl transcriptional activity is reduced in K562 cells under oxygen shortage. The SUnSET assay showed an overall reduction of protein synthesis under oxygen/glucose shortage in both cell lines. However, only low oxygen decreased polysome-associated BCR/abl mRNA significantly in KCL22 cells, suggesting a decreased BCR/Abl translation. The proteasome inhibitor MG132 or the pan-caspase inhibitor z-VAD-fmk extended BCR/Abl expression under oxygen/glucose shortage in K562 cells. Glucose shortage induced autophagy-dependent BCR/Abl protein degradation in KCL22 cells. Overall, our results showed that energy restriction induces different cell-specific BCR/Abl protein suppression patterns, which represent a converging route to TKi-resistance of CML cells. Thus, the interference with BCR/Abl expression in environment-adapted CML cells may become a useful implement to current therapy.
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