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

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 (HIF1a) and activates HIF1a signaling by regulating iron concentration.When ABCB7 expression is maintained high in cancer cells, hypoxia-independent activation of HIF1a 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 HIF1a 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 nonapoptotic cell death via maintenance of iron homeostasis and hypoxia-independent HIF1a signaling.