BCL-2 selective inhibitor ABT-199 primes rhabdomyosarcoma cells to histone deacetylase inhibitor-induced apoptosis

• Published in: Oncogene Vol. 37; no. 39; pp. 5325 - 5339
• Main Authors: Heinicke, Ulrike, Haydn, Tinka, Kehr, Sarah, Vogler, Meike, Fulda, Simone
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2018; Nature Publishing Group
• Subjects: 631/67/1059/602; 631/80/82/23; 96; 96/2; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis; Apoptosis - drug effects; BAX protein; Bcl-2 protein; BIM protein; Biochemistry; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Cancer; Cancer treatment; Care and treatment; Caspase; Cell Biology; Cell death; Cell Line, Tumor; Cellular proteins; Chromatin; Development and progression; Drug Synergism; Enzyme inhibitors; Genetic aspects; Health aspects; Histone deacetylase; Histone Deacetylase Inhibitors - pharmacology; Human Genetics; Humans; Hydroxamic Acids - pharmacology; Internal Medicine; Mcl-1 protein; Medicine; Medicine & Public Health; Membrane potential; Mitochondria; Oncology; Proteins; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Rhabdomyosarcoma; Sulfonamides - pharmacology; Therapeutics; Tumors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-018-0212-5

BH3 mimetics are emerging novel anticancer therapeutics that potently and specifically inhibit antiapoptotic BCL-2 proteins and thereby induce cell death in many cancer entities. Previously, we demonstrated that JNJ-26481585 (JNJ), a second-generation histone deacetylase inhibitor (HDACI), engages mitochondrial apoptosis via upregulation of several BH3-only proteins. In the present study, we describe synergistic interactions of JNJ with BH3 mimetics (i.e. ABT-737, ABT-199) in rhabdomyosarcoma (RMS) cells. Importantly, JNJ synergizes with ABT-199 to trigger apoptosis in primary-derived RMS cells isolated from tumor samples, underlining the translational importance of combining these compounds and their potential to improve cancer therapy. Importantly, JNJ/ABT-199 cotreatment also significantly inhibits long-term survival of RMS cells. Mechanistically, JNJ increases expression levels of the BH3-only protein BIM, while exposure to ABT-199 displaces BIM from BCL-2 and shuttles BIM to MCL-1, which also constitutively sequesters NOXA. Both BIM and NOXA contribute to JNJ/ABT-199-mediated cell death, as individual knockdown of NOXA or BIM significantly prevents cell death. Further, JNJ and ABT-199 act in concert to activate BAK and BAX, resulting in loss of the mitochondrial membrane potential (MMP) and caspase activation. These events are required for JNJ/ABT-199-mediated apoptosis, since BAK or BAX silencing or inhibition of caspases significantly protects from JNJ/ABT-199-induced cell death. Rescue experiments demonstrate that overexpression of MCL-1, but not overexpression of BCL-2, blocks JNJ/ABT-199-induced apoptosis. In conclusion, this study provides the first demonstration of ABT-199-induced priming, which sensitizes RMS cells to HDACI, such as JNJ, by engaging mitochondrial apoptosis, highlighting that BH3 mimetics show great promise for the treatment of RMS.