image: 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.
Credit: 2024 Tian and El-Deiry
“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
Video Short: https://www.youtube.com/watch?v=eBp_UGrkii8
Keywords: cancer, mutant p53, integrated stress response (ISR), ATF4, HRI, ClpP
Click here to sign up for free Altmetric alerts about this article.
About Oncotarget:
Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.
Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).
To learn more about Oncotarget, visit Oncotarget.com and connect with us on social media:
X
Facebook
YouTube
Instagram
LinkedIn
Pinterest
Spotify, and available wherever you listen to podcasts
Click here to subscribe to Oncotarget publication updates.
For media inquiries, please contact media@impactjournals.com.
Oncotarget Journal Office
6666 East Quaker St., Suite 1
Orchard Park, NY 14127
Phone: 1-800-922-0957 (option 2)
Journal
Oncotarget
Method of Research
News article
Subject of Research
Not applicable
Article Title
Integrated stress response (ISR) activation and apoptosis through HRI kinase by PG3 and other p53 pathway-restoring cancer therapeutics
Article Publication Date
17-Sep-2024
COI Statement
W.S.E-D. is a co-founder of Oncoceutics, Inc., a subsidiary of Chimerix, p53-Therapeutics, Inc., and SMURF-Therapeutics, Inc. Dr. El-Deiry has disclosed his relationships with Oncoceutics/Chimerix, p53-Therapeutics, Inc., and SMURF-Therapeutics and potential conflicts of interest to his academic institution/employer and is fully compliant with NIH and institutional policy that is managing this potential conflict of interest.