article = {COR-2020-7-112}
title = {ApoL6 Induces Dichotomous Cell Death Phenotype Involving Both Apoptosis and Necroptosis in Cancer Cells}
journal = {Clinical Oncology and Research}
year = {2020}
issn = {2613-4942}
doi = {http://dx.doi.org/10.31487/j.COR.2020.07.12}
url = {https://www.sciencerepository.org/apol6-induces-dichotomous-cell-death-phenotype-involving-both-apoptosis-and_COR-2020-7-112 
author = {Isabella  Murphy,Guanghua  Wan,Shulin  Fu,Yulan  Liu,Yinsheng  Qiu,Thomas  Ma,Warren  Laskey,Hitendra  Chand,Larry  Sklar,Chien-An Andy Hu,}
keywords = {ApoL6, apoptosis, necroptosis, MLKL, IL-1β}
abstract ={Apolipoprotein L6 (ApoL6) is a pro-death, BH3-only and phospholipid-binding member of the Bcl-2
family. Previously, we showed that ectopic expression of ApoL6 induces mitochondria-mediated apoptosis.
In this study, we hypothesized that ApoL6 plays a dichotomous role in regulated cell death (RCD) pathways
that involves both apoptosis and necroptosis. Necroptosis, or programmed necrosis, can occur
simultaneously or alternatively to apoptosis as a caspase-independent pathway, and is characterized by the
formation of intracellular necrosomes and plasma membrane pores. The pseudokinase mixed lineage kinase
domain-like protein (MLKL) interacts with the necrosome to become phosphorylated and activated.
Phosphorylated (p-) MLKL molecules migrate to the plasma membrane to form pores, disrupt membrane
integrity, and selectively release intracellular components. The proinflammatory cytokine IL-1β is amongst
a number of molecules released in this process. To investigate the role of ApoL6 in RCD, ApoL6 was
overexpressed via a Tet-Off gene inducible system in a p53 null colorectal cancer cell line DLD-1.
Necroptotic cell death was marked by an increased level of intracellular and plasma membrane p-MLKL
and extracellular release of IL-1β along with the disruption of the plasma membrane. We found that in the
presence of apoptotic inhibitors, levels of necroptotic cell death increased, indicating an enhanced push
away from apoptosis. We also showed that ApoL6 preferentially binds with phosphatidylinositol phosphate
species (PIPs), which include PI (4,5) P2, PI4P and PI5P. Thus, we expand on the role of ApoL6 in RCD to
induce a mixed cell-death phenotype that includes both apoptosis and necroptosis.
}