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

Oncogene volume 37, pages 5325–5339 (2018)Cite this article

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Abstract

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.

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Acknowledgements

We thank D. Bruecher for expert technical assistance and C. Hugenberg for excellent secretarial assistance. This work has been partially supported by grants from the BMBF, the Deutsche Krebshilfe and the Deutsche Kinderkrebsstiftung (to SF) and a grant from the Medical Faculty, Goethe-University Frankfurt (to MV).

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Author notes

  1. These authors contributed equally: Ulrike Heinicke, Tinka Haydn.

  2. These authors jointly supervised this work: Meike Vogler, Simone Fulda.

Authors and Affiliations

  1. Institute for Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt, Komturstr. 3a, 60528, Frankfurt, Germany

    Ulrike Heinicke, Tinka Haydn, Sarah Kehr, Meike Vogler & Simone Fulda

  2. German Cancer Consortium (DKTK) Partner Site, Frankfurt, Germany

    Tinka Haydn & Simone Fulda

  3. German Cancer Research Center (DKFZ), Heidelberg, Germany

    Tinka Haydn & Simone Fulda

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  1. Ulrike Heinicke
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Correspondence to Simone Fulda.

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Heinicke, U., Haydn, T., Kehr, S. et al. BCL-2 selective inhibitor ABT-199 primes rhabdomyosarcoma cells to histone deacetylase inhibitor-induced apoptosis. Oncogene 37, 5325–5339 (2018). https://doi.org/10.1038/s41388-018-0212-5

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