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Fig. 2 | Journal of Experimental & Clinical Cancer Research

Fig. 2

From: Hypoxia, endoplasmic reticulum stress and chemoresistance: dangerous liaisons

Fig. 2

Hypoxia induces chemoresistance. Besides the stabilization of the hypoxia-inducible factor-1α (HIF-1α) due to the low activity of prolyl hydroxylase dioxygenase (PHDs) enzymes, oncogenically activated axes downstream receptor tyrosine kinases, such as PI3K/Akt/mTOR and Ras/Raf/MAPK axes, contribute to increase the amount of transcriptionally active HIF-1α. Among the target genes there are several ATP binding cassette (ABC) transporters involved in chemotherapeutic drug efflux (e.g. ABC transporter B1/multidrug resistance 1, ABCB1/MDR1, encoding for P-glycoprotein; ABC transporter C1/multidrug drug resistance related protein 1, ABCC1/MRP1; ABC transporter G2/breast cancer resistance protein, ABCG2/BCRP; lung resistance protein, LRP), and genes involved in DNA repair, such as topoisomerase 2A (TOP2A), DNA-PK, Ku-70 and Ku-80, preventing the DNA damage elicited by chemotherapy. HIF-1α also inhibits TP53-induced apoptosis in repsonse to chemotherapy, by destabilizing TP53. In addition, hypoxia is associated with other events determining chemoresistance, such as the increase in mitophagy that spares ATP, the reduction of oxidative phosphorylation (OXPHOS) and reactive oxygen species (ROS) that reduce oxidative damage, the increase of the anti-apoptotic proteins Bcl-2 and IAP3. The sum of these hypoxia-driven responses, either HIF-1α-dependent or independent, make hypoxic cells highly chemoresistant

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