Abstract 2541: Heterogeneity of VDAC2-Bak/Bax mediated mitochondrial apoptosis can be exploited to develop effective and selective treatment against metastatic uveal melanoma

Abstract

Abstract Apoptosis, a form of programmed cell death, is an evolutionarily conserved and genetically regulated phenomenon that is pivotal in maintaining tissue homeostasis and is an important player in regulating carcinogenesis. Mitochondria along with its resident proteins are the central player in regulating apoptosis. In recent years, VDAC2, an Outer Mitochondrial Membrane (OMM) protein has been shown to be the key recruitment factor for Bak, a pro-apoptotic protein to the OMM and, therefore is crucial for tBid-induced OMM permeabilization. We have previously found that unexpectedly, hepatocellular carcinoma (HCC) cells are vastly more sensitive to tBid induced apoptosis compared to normal hepatocytes and this difference is owed to high abundance of VDAC2-Bak in HCC. These findings are in line with multiple datasets posted in Oncomine, and protein atlas websites and may have clinical relevance. Combination of S63845, a selective Mcl-1 inhibitor, with TRAIL was effective at reducing tumor growth in vivo, but only in tumors expressing VDAC2. We hypothesized that the liver metastases of some extrahepatic primary tumors might also show enhanced sensitivity to VDAC2-Bak mediated apoptosis as compared to the normal liver tissue. Testing this hypothesis is important for uveal melanoma (UM) that primarily metastasizes in the liver, and these metastases lack an effective treatment. Interestingly, on testing several UM cell lines and patient samples we observed that VDAC2-Bak are upregulated in UM liver metastasis as well as compared to normal liver tissue. As expected, high VDAC2 expressing cell lines were also more sensitive to tBid induced OMM permeabilization. We propose that these differences can be exploited to design an effective therapy for metastasized UM. Citation Format: Piyush Mishra. Heterogeneity of VDAC2-Bak/Bax mediated mitochondrial apoptosis can be exploited to develop effective and selective treatment against metastatic uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2541.