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Review
, 9, 1421
eCollection

Predisposition to Apoptosis in Hepatocellular Carcinoma: From Mechanistic Insights to Therapeutic Strategies

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Review

Predisposition to Apoptosis in Hepatocellular Carcinoma: From Mechanistic Insights to Therapeutic Strategies

Jens U Marquardt et al. Front Oncol.

Abstract

Hepatocellular carcinoma (HCC) ranks among the most rapidly evolving cancers in the Western world. The majority of HCCs develop on the basis of a chronic inflammatory liver damage that predisposes liver cancer development and leads to deregulation of multiple cellular signaling pathways. The resulting dysbalance between uncontrolled proliferation and impaired predisposition to cell death with consecutive failure to clear inflammatory damage is a key driver of malignant transformation. Therefore, resistance to death signaling accompanied by metabolic changes as well as failed immunological clearance of damaged pre-neoplastic hepatocytes are considered hallmarks of hepatocarcinogenesis. Hereby, the underlying liver disease, the type of liver damage and individual predisposition to apoptosis determines the natural course of the disease as well as the therapeutic response. Here, we will review common and individual aspects of cell death pathways in hepatocarcinogenesis with a particular emphasis on regulatory networks and key molecular alterations. We will further delineate the potential of targeting cell death-related signaling as a viable therapeutic strategy to improve the outcome of HCC patients.

Keywords: BCL-2 family; BH3; BH3 profiling; cell death; hepatocellular carcinoma; inflammation; mitochondrial apoptosis; primed to death.

Figures

Figure 1
Figure 1
Strategies to analyze apoptotic predisposition based on BCL-2 proteins. (A) BAX level. The right cell contains more BAX (blue) than the left and is therefore considered to have a higher apoptosis predisposition. Other relevant factors are not measured. (B) BAX vs. BCL-xL level. The ratio between BAX and a single pro-survival BCL-2 protein (BCL-xL, red) is similar in both cells. Therefore, both cells would be judged to have the same tendency to initiate apoptosis. The redundancy of the BCL-2 family would require this analysis to be expanded to all BCL-2 proteins in order to be insightful. (C) BH3 profiling. Permeabilized and cultured cells are incubated with BH3 peptides (green star) in order to titrate the amount of free BH3 binding sites on the outer mitochondrial membrane (OMM). BH3-only proteins (green) associated with the OMM following prior cell stress reduce the amount of free BH3 binding sites and thus increase the sensitivity toward BH3 mimetics. The increased capacity of the left cell would translate into a reduced sensitivity toward BH3 mimetics. (D) Relative BAX localization. Determination of the cytosolic and mitochondrial BAX pools in intact cells describes the position of the BAX localization equilibrium and thus the cellular predisposition to apoptosis. While single contributing factors cannot be dissected, all contributing factors, e.g., BCL-2 protein interactions with BH3 motifs and other segments, interacting proteins outside the BCL-2 family, are included. BH3-only proteins reduce the shuttling rate and thus the cytosolic BAX pool. The larger cytosolic pool of the left cell shows reduced predisposition to apoptosis. The analysis can be supplemented with measuring the functionally redundant and similarly regulated BAK, which is usually shifted toward the mitochondria but shows a similar range of localizations in human samples.
Figure 2
Figure 2
Mitochondrial apoptosis signaling. Mitochondrial apoptosis is regulated by members of the BCL-2 protein family on the outer mitochondrial membrane (OMM). The pro-apoptotic BCL-2 proteins BAX and BAK (blue) constantly translocate to the OMM undergoing a conformational change. The porin voltage-dependent anion channel 2 (VDAC 2, purple) acts as mitochondrial BAX/BAK receptor and as platform for the retrotranslocation of BAX and BAK back into the cytosol dependent on the activities of pro-survival BCL-2 proteins (red). The equilibrium between BAX/BAK translocation and retrotranslocation determines the cellular predisposition to apoptosis. Intrinsic stress as well as death receptor signaling is mediated by BH3-only proteins (yellow) that inhibit BAX/BAK retrotranslocation shifting BAX and BAK toward the mitochondria. The BH3-only proteins tBID, BIM and PUMA are also thought to directly activate BAX and BAK initiating OMM permeabilization and the release of cytochrome c (cyt c) and SMAC into the cytosol. This function can be inhibited by pro-survival BCL-2 proteins. Cytosolic cyt c initiates in turn the formation of the apoptosome (green), an APAF-1 complex activating Caspase 9 (Cas 9). Subsequently, Caspases 3 and 7 are activated that can be inhibited by IAPs in the absence of SMAC in the cytosol. Caspase 3/7 activation leads to the efficient dismantling of the cell into apoptotic bodies that are later phagocytosed.

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