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Article

BAX Redistribution Induces Apoptosis Resistance and Selective Stress Sensitivity in Human HCC

by
Kathrin Funk
1,2,†,
Carolin Czauderna
3,†,
Ramona Klesse
1,2,
Diana Becker
3,
Jovana Hajduk
3,
Aline Oelgeklaus
1,2,4,
Frank Reichenbach
1,4,
Franziska Fimm-Todt
1,
Joachim Lauterwasser
1,
Peter R. Galle
3,
Jens U. Marquardt
5,* and
Frank Edlich
1,6,*
1
Institute for Biochemistry and Molecular Biology, University of Freiburg, 79104 Freiburg, Germany
2
Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany
3
Department of Medicine, Lichtenberg Research Group, University Mainz, 55116 Mainz, Germany
4
Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, 79104 Freiburg, Germany
5
Department of Medicine I, University Hospital Schleswig-Holstein, Ratzeburger Allee 160, 23562 Lübeck, Germany
6
CIBSS Centre for Integrative Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2020, 12(6), 1437; https://doi.org/10.3390/cancers12061437
Submission received: 19 May 2020 / Accepted: 27 May 2020 / Published: 31 May 2020
(This article belongs to the Collection Cancer Biomarkers)
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Abstract

Cancer therapies induce differential cell responses, ranging from efficient cell death to complete stress resistance. The BCL-2 proteins BAX and BAK govern the cellular decision between survival and mitochondrial apoptosis. Therefore, the status of BAX/BAK regulation can predict the cellular apoptosis predisposition. Relative BAX/BAK localization was analyzed in tumor and corresponding non-tumor samples from 34 hepatocellular carcinoma (HCC) patients. Key transcriptome changes and gene expression profiles related to the status of BAX regulation were applied to two independent cohorts including over 500 HCC patients. The prediction of apoptotic response was tested using cell lines and polyclonal tumor isolates. Cellular protection from BAX was confirmed by challenging cells with mitochondrial BAX. We discovered a subgroup of HCC with selective protection from BAX-dependent apoptosis. BAX-protected tumors showed enrichment of signaling pathways associated with oxidative stress response and DNA repair as well as increased genetic heterogeneity. Gene expression profiles characteristic to BAX-specific protection are enriched in poorly differentiated HCCs and show significant association to the overall survival of HCC patients. Consistently, addiction to DNA repair of BAX-protected cancer cells caused selective sensitivity to PARP inhibition. Molecular characteristics of BAX-protected HCC were enriched in cells challenged with mitochondrial BAX. Our results demonstrate that predisposition to BAX activation impairs tumor biology in HCC. Selective BAX inhibition or lack thereof delineates distinct subgroups of HCC patients with molecular features and differential response pattern to apoptotic stimuli and inhibition of DNA repair mechanisms.
Keywords: BCL-2 family; BH3; mitochondrial apoptosis; DNA damage; BH3 profiling BCL-2 family; BH3; mitochondrial apoptosis; DNA damage; BH3 profiling

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MDPI and ACS Style

Funk, K.; Czauderna, C.; Klesse, R.; Becker, D.; Hajduk, J.; Oelgeklaus, A.; Reichenbach, F.; Fimm-Todt, F.; Lauterwasser, J.; Galle, P.R.; et al. BAX Redistribution Induces Apoptosis Resistance and Selective Stress Sensitivity in Human HCC. Cancers 2020, 12, 1437. https://doi.org/10.3390/cancers12061437

AMA Style

Funk K, Czauderna C, Klesse R, Becker D, Hajduk J, Oelgeklaus A, Reichenbach F, Fimm-Todt F, Lauterwasser J, Galle PR, et al. BAX Redistribution Induces Apoptosis Resistance and Selective Stress Sensitivity in Human HCC. Cancers. 2020; 12(6):1437. https://doi.org/10.3390/cancers12061437

Chicago/Turabian Style

Funk, Kathrin, Carolin Czauderna, Ramona Klesse, Diana Becker, Jovana Hajduk, Aline Oelgeklaus, Frank Reichenbach, Franziska Fimm-Todt, Joachim Lauterwasser, Peter R. Galle, and et al. 2020. "BAX Redistribution Induces Apoptosis Resistance and Selective Stress Sensitivity in Human HCC" Cancers 12, no. 6: 1437. https://doi.org/10.3390/cancers12061437

APA Style

Funk, K., Czauderna, C., Klesse, R., Becker, D., Hajduk, J., Oelgeklaus, A., Reichenbach, F., Fimm-Todt, F., Lauterwasser, J., Galle, P. R., Marquardt, J. U., & Edlich, F. (2020). BAX Redistribution Induces Apoptosis Resistance and Selective Stress Sensitivity in Human HCC. Cancers, 12(6), 1437. https://doi.org/10.3390/cancers12061437

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