title: Different BCR/Abl protein suppression patterns as a converging trait of chronic myeloid leukemia cell adaptation to energy restriction.
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.
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences "Mario Serio", Università degli Studi di Firenze, Florence, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bono
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences "Mario Serio", Università degli Studi di Firenze, Florence, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Lulli
authors.affiliation: Centre For Integrative Biology (CIBIO), Università degli Studi di Trento, Trento, Italy.
authors.forename: Vito Giuseppe
authors.initials: VG
authors.lastname: D'Agostino
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences "Mario Serio", Università degli Studi di Firenze, Florence, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Di Gesualdo
authors.affiliation: Centre For Integrative Biology (CIBIO), Università degli Studi di Trento, Trento, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Loffredo
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences "Mario Serio", Università degli Studi di Firenze, Florence, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Cipolleschi
authors.affiliation: Centre For Integrative Biology (CIBIO), Università degli Studi di Trento, Trento, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Provenzani
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences "Mario Serio", Università degli Studi di Firenze, Florence, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Rovida
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences "Mario Serio", Università degli Studi di Firenze, Florence, Italy.
authors.forename: Persio
authors.initials: P
authors.lastname: Dello Sbarba
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D063646:Carcinogenesis; D019008:Drug Resistance, Neoplasm; D004734:Energy Metabolism; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics; D016374:Oncogene Proteins v-abl / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D059748:Proteolysis; D051562:Proto-Oncogene Proteins c-bcr / Q000235:genetics; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents; D016374:Oncogene Proteins v-abl; D047428:Protein Kinase Inhibitors; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr; D046988:Proteasome Endopeptidase Complex; D005947:Glucose
keywords: glucose shortage; hypoxia; post-translational regulation; transcriptional regulation; translational regulation