title: BMX Negatively Regulates BAK Function, Thereby Increasing Apoptotic Resistance to Chemotherapeutic Drugs.
abstract: The ability of chemotherapeutic agents to induce apoptosis, predominantly via the mitochondrial (intrinsic) apoptotic pathway, is thought to be a major determinant of the sensitivity of a given cancer to treatment. Intrinsic apoptosis, regulated by the BCL2 family, integrates diverse apoptotic signals to determine cell death commitment and then activates the nodal effector protein BAK to initiate the apoptotic cascade. In this study, we identified the tyrosine kinase BMX as a direct negative regulator of BAK function. BMX associates with BAK in viable cells and is the first kinase to phosphorylate the key tyrosine residue needed to maintain BAK in an inactive conformation. Importantly, elevated BMX expression prevents BAK activation in tumor cells treated with chemotherapeutic agents and is associated with increased resistance to apoptosis and decreased patient survival. Accordingly, BMX expression was elevated in prostate, breast, and colon cancers compared with normal tissue, including in aggressive triple-negative breast cancers where BMX overexpression may be a novel biomarker. Furthermore, BMX silencing potentiated BAK activation, rendering tumor cells hypersensitive to otherwise sublethal doses of clinically relevant chemotherapeutic agents. Our finding that BMX directly inhibits a core component of the intrinsic apoptosis machinery opens opportunities to improve the efficacy of existing chemotherapy by potentiating BAK-driven cell death in cancer cells.
authors: Department of Oncology, WIMM, University of Oxford, Oxford, United Kingdom. Jf211@le.ac.uk astorey62@gmail.com.
authors: Joanna L
authors: JL
authors: Fox
authors: Department of Oncology, WIMM, University of Oxford, Oxford, United Kingdom. Jf211@le.ac.uk astorey62@gmail.com.
authors: Alan
authors: A
authors: Storey
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001943:Breast Neoplasms; D002166:Camptothecin / Q000494:pharmacology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C494772:BAK1 protein, human; D050998:bcl-2 Homologous Antagonist-Killer Protein; D005047:Etoposide; C492367:BMX protein, human; D011505:Protein-Tyrosine Kinases; C409985:PTPN21 protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D002166:Camptothecin
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