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Fig. 8 | Journal of Experimental & Clinical Cancer Research

Fig. 8

From: Mitochondrial ROS drive resistance to chemotherapy and immune-killing in hypoxic non-small cell lung cancer

Fig. 8

Mitochondrial ROS induce chemo-immune-resistance in hypoxic tumors by up-regulating the HIF-1α/C/EBP-β axis. a Intermittent hypoxia, often experimented by solid tumors, reduces the efficiency of mitochondrial electron transport chain, increases mitochondrial depolarization and damage, leading to the high production of reactive oxygen species (ROS). Mitochondrial ROS stabilize the interaction of the hypoxia-inducible factor-1α (HIF-1α) with the mRNA of the transcription factor CCAAT enhancer binding protein beta (C/EBP-β). This interaction increases C/EBP-β LAP and decreases C/EBP-β LIP isoform. LAP up-regulates ABCB1 and ABCC1, and decrease ABCA1 at transcriptional level. The high levels of ABCB1 and ABCC1 induce the efflux of chemotherapeutic drugs (d), causing chemoresistance. The low level of ABCA1 prevents the efflux of isopentenyl pyrophosphate (IPP) and the activation of the anti-tumor Vγ9Vδ2 T-cells, determining immuno-resistance. b Scavenging mitochondrial ROS with mitoquinol (mitoQ) disrupts the HIF-1α C/EBP-β axis, increases the LIP/LAP ratio, decreasing the drug efflux transporters ABCB1 and ABCC1, and increasing the immuno-sensitizer transporter ABCA1. As a result, hypoxic cells were more sensitive to chemotherapy and to Vγ9Vδ2 T-cell immune-killing

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