Integrated stress response (ISR) activation and apoptosis through HRI kinase by PG3 and other p53 pathway-restoring cancer therapeutics (IMAGE)

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Integrated stress response (ISR) activation and apoptosis through HRI kinase by PG3 and other p53 pathway-restoring cancer therapeutics

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Figure 8: Inhibition of heme biosynthesis leads to upregulation of ATF4.

(A) HT29 cells were treated with SA and ONC201 for 20 hours. Western blotting was performed using the indicated antibodies. (B) HT29 cells were transfected with siCtrl, siHRI, siClpX, siALAS1, siClpX/siALAS1 and siClpX/siALAS1/siHRI for 48 hours. (C) HT29 cells were transfected with siCtrl, siLonP1, siClpP for 24 or 48 hours respectively, and then treated with ONC201 for 24 hours. (D) Proposed model of ONC201-induced cell apoptosis through ClpP/ALAS1/HRI/ATF4 axis. (E, F) Silencing of ClpP in HCT116 p53−/− and MDA-MB-468 cells and then treated with PG3, PG3-Oc and ONC201. Western blot was performed using indicated antibodies.

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2024 Tian and El-Deiry

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