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

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.

SUBMITTER: Funk K

PROVIDER: S-EPMC7352885 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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

Funk Kathrin K Czauderna Carolin C Klesse Ramona R Becker Diana D Hajduk Jovana J Oelgeklaus Aline A Reichenbach Frank F Fimm-Todt Franziska F Lauterwasser Joachim J Galle Peter R PR Marquardt Jens U JU Edlich Frank F

Cancers 20200531 6

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 expressio ...[more]

PMID: 32486514

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Project description:Cancer pain is an important factor affecting life quality of patients especially in the advanced stage and relieving pain is one of fundamental strategies for cancer treatment. Opioids such as morphine are the most widely used in clinics. However, they have been reported to be associated with the occurrence and development of several types of cancer. Thus, search for an opioid that has analgesic effect and can retard cancer progress simultaneously is critical for cancer management. In this study, we first examined the expression of μ and κ (MOR and KOR) in cell lines and tumor tissues of hepatocellular carcinoma (HCC), a malignant tumor with high mortality, and then compared the effects of opioid receptors-specific agonists on malignant phenotypes of HCC cells in vitro and tumor growth in an HCC xenograft mouse model. KOR and MOR were found to be highly expressed in HCC cell lines and HCC tissues. The KOR-specific agonist U50488h, oxycodone (agonist for both KOR and MOR) and the MOR-specific agonist morphine inhibited HCC cell proliferation, while only U50488h and oxycodone suppressed colony formation and migration of HCC cells. U50488h and oxycodone, but not morphine, induced HCC apoptosis. Further detection of PERK, GRP78 and CHOP revealed that PERK signaling was upregulated by treatment with U50488h, while treatment with the PERK inhibitor GSK2656157 partially reversed the promotion of apoptosis and inhibition of cell proliferation by U50488h, indicating that endoplasmic reticulum stress is associated with its suppressing effect on HCC malignant phenotypes. Similar to the in vitro results, HCC growth was significantly reduced by administration of U50488h and oxycodone, but not by morphine, in the HCC xenograft mouse model. PERK and caspase-3 in the HCC tissues were up-regulated by U50488h treatment as detected by immunohistochemistry and western blotting. Taken together, our results revealed that activation of KOR by U50488h inhibited malignant phenotypes of HCC both in vitro and in vivo, while activation of MOR by morphine did not have such effect. Because of their dual roles in the relief of pain and in the suppression of malignant phenotypes, opioids such as U50488h that act on KOR should be considered as the first choice for HCC management.

Dataset Information

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

Publications

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

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