95PABCB7 is a gatekeeper of both programmed cell death, apoptotic and non-apoptotic cell death

Abstract Background The ATP-binding cassette (ABC) transporters are superfamily proteins of cellular translocation machinery. Many ABC transporters release drugs to give multidrug resistance. However, ABC transporters existing in intracellular compartments give drug resistance by regulating biological processes, rather than direct release of drugs. The current study aimed to investigate the molecular mechanism that causes the drug resistance of the mitochondrial ABC transporters in cancer cells. Methods RNA-sequencing and bioinformatics analyses were performed to identify key mitochondrial ABC transporters and ABC transporter subfamily B member 7 (ABCB7)-mediated transcriptomic alterations. We investigated role of ABCB7 in iron homeostasis by examining iron concentration and reactive oxygen species (ROS) generation. Drug resistance and cellular survival mechanisms were understood by comparing the type and degree of cell death according to the ABCB7 expression. Results ABCB7 is highly expressed in patients with glioblastoma and has a negative correlation with prognosis. The increase in ABCB7 gives resistance to drug and the loss of ABCB7 leads to cell death. ABCB7 increases the expression of hypoxia-inducible factor 1 alpha (HIF1α) and activates HIF1α signaling by regulating iron concentration. When ABCB7 expression is maintained high in cancer cells, hypoxia-independent activation of HIF1α inhibits cell death by suppressing leucine zipper downregulated in cancer 1 (LDOC1). However, when ABCB7 is decreased, non-apoptotic cell death is induced by the change of iron concentration, and apoptosis which is inhibited by HIF1α signal is also induced. Additionally, because ABCB7 is essential for survival of universal cancer cells, it is presented as a pan-cancer core fitness gene. Conclusions Our findings demonstrate the ABCB7 inhibits both apoptotic and non-apoptotic cell death via maintenance of iron homeostasis and hypoxia-independent HIF1α signaling. Editorial acknowledgement Cancer Growth Regulation Laboratory for their discussion and technical assistance. Legal entity responsible for the study The authors. Funding National Research Foundation of Korea (NRF) [grant numbers: 2015R1A5A1009024 and 2017R1E1A1A01074205], the School of Life Sciences and Biotechnology for BK21 Plus, Korea University and Institute of Animal Molecular Biotechnology Korea University. Disclosure All authors have declared no conflicts of interest.