ISR Activation & Apoptosis via HRI Kinase by PG3 and Other p53 Cancer Therapies

“Our results provide unique insights into the mechanism of action of PG3 as a novel cancer therapeutic targeting p53 pathway-like tumor suppression.”

BUFFALO, NY- September 18, 2024 – A new research paper was published in Oncotarget's Volume 15 on September 17, 2024, entitled, “Integrated stress response (ISR) activation and apoptosis through HRI kinase by PG3 and other p53 pathway-restoring cancer therapeutics.”

As highlighted in the abstract of this study, restoration of the p53 pathway has been a long-term goal in cancer research to treat tumors with mutated p53 and aggressive clinical behavior. Additionally, p53 pathway restoration in p53-deficient cancers can be achieved by small molecules via p53-dependent or p53-independent processes.

Researchers Xiaobing Tian and Wafik S. El-Deiry from Brown University, compare the activation of p53 target genes by the novel compounds PG3 and PG3-Oc, which activate these genes in a p53-independent manner, with four compounds that activate mutant p53. Nutlin-3a is used as a negative control. 

The authors note that PG3 and PG3-Oc upregulate p21, PUMA, and DR5 in five cancer cell lines with various p53 mutational statuses through ATF4 (Activating Transcriptional Factor 4) and the integrated stress response (ISR), independent of p53. Mutant p53-targeting compounds induce the expression of the three major downstream p53 target genes and ATF4 in a highly variable, cell-type-dependent manner. They also note that PUMA mediates apoptosis through the activation of caspase-8 in HT29 cells and potentially caspase-10 in SW480 cells.

This study reveals a novel mechanism by which PG3 induces cell death via the HRI/ATF4/PUMA axis.

“Our work provides evidence that PG3 shows the same potency as PG3-Oc, and utilizes the same mechanisms of restoration of p53 target gene activation and ATF4-mediated apoptosis as PG3-Oc.”

Continue reading: DOI: https://doi.org/10.18632/oncotarget.28637

Correspondence to: Wafik S. El-Deiry - wafik@brown.edu

Keywords: cancer, mutant p53, integrated stress response (ISR), ATF4, HRI, ClpP

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