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.

Notoginsenoside R1 induces DNA damage via PHF6 protein to inhibit cervical carcinoma cell proliferation

“…Apoptosis, a widespread phenomenon that occurs in the developmental stages of prokaryotic and eukaryotic cells, is controlled by specific genes, such as caspase-3, caspase-9, Bcl-2 and Bax ( 21 , 24 , 37 – 39 ). It also plays a pivotal role in biological evolution, embryonic development and dynamic homeostatic balance maintenance ( 40 , 41 ).…”

“…In addition, NGR1, as a immunologic adjuvant to enhance immunity (35,36), may serve as a beneficial candidate for chemotherapy to treat cervical carcinoma. Apoptosis, a widespread phenomenon that occurs in the developmental stages of prokaryotic and eukaryotic cells, is controlled by specific genes, such as caspase-3, caspase-9, Bcl-2 and Bax (21,24,(37)(38)(39). It also plays a pivotal role in biological evolution, embryonic development and dynamic homeostatic balance maintenance (40,41).…”

An atlas of inter- and intra-tumor heterogeneity of apoptosis competency in colorectal cancer tissue at single cell resolution

“…While we here consider the levels of 9 apoptosis markers, we did not take into account proteins' state such as BCL2's phosphorylation status (Ruvolo et al, 2001) nor subcellular localization of proteins which is possible to account for with the Cell DIVE™ platform. For example, BAX's localization at the mitochondria or in the cytosol was reported to be clinically relevant in acute myeloid leukemia (Reichenbach et al, 2017) and hepatocellular carcinoma (Funk et al, 2020). BAX localization could be considered by including a mitochondrial marker, or by analyzing the BAX signal within the cytosolic cell mask, with an evenly distributed signal suggesting cytosolic localization, and uneven distribution suggesting localization at mitochondria.…”

Transferrin-Conjugated Erianin-Loaded Liposomes Suppress the Growth of Liver Cancer by Modulating Oxidative Stress

“…One of the key biochemical changes in the development of liver cancer occurs in the network of B-cell lymphoma-2 (Bcl-2) family proteins, which results in the compensatory generation of anti-apoptotic effectors (6). The activation of Bcl-2 associated X protein (Bax) and Bcl-2 homologous antagonist/killer (Bak) protein induces outer mitochondrial membrane permeability and caspase cascade activity (6). Caspase-3 is a crucial proapoptotic protein in caspase cascades, and is therefore considered to be a key factor of mitochondrial apoptosis (7).…”