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Tian X , Ahsan N , Lulla A , Lev A , Abbosh P , Dicker DT , Zhang S , El-Deiry WS
P53-independent partial restoration of the p53 pathway in tumors with mutated p53 through ATF4 transcriptional modulation by ERK1/2 and CDK9
Neoplasia. 2021 Feb 11;23(3) :304-325
PMID: 33582407    PMCID: PMC7890376    URL: https://www.ncbi.nlm.nih.gov/pubmed/33582407
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Abstract
A long-term goal in the cancer-field has been to develop strategies for treating p53-mutated tumors. A novel small-molecule, PG3-Oc, restores p53 pathway-signaling in tumor cells with mutant-p53, independently of p53/p73. PG3-Oc partially upregulates the p53-transcriptome (13.7% of public p53 target-gene dataset; 15.2% of in-house dataset) and p53-proteome (18%, HT29; 16%, HCT116-p53(-/-)). Bioinformatic analysis indicates critical p53-effectors of growth-arrest (p21), apoptosis (PUMA, DR5, Noxa), autophagy (DRAM1), and metastasis-suppression (NDRG1) are induced by PG3-Oc. ERK1/2- and CDK9-kinases are required to upregulate ATF4 by PG3-Oc which restores p53 transcriptomic-targets in cells without functional-p53. PG3-Oc represses MYC (ATF4-independent), and upregulates PUMA (ATF4-dependent) in mediating cell death. With largely nonoverlapping transcriptomes, induced-ATF4 restores p53 transcriptomic targets in drug-treated cells including functionally important mediators such as PUMA and DR5. Our results demonstrate novel p53-independent drug-induced molecular reprogramming involving ERK1/2, CDK9, and ATF4 to restore upregulation of p53 effector genes required for cell death and tumor suppression.
Notes
1476-5586 Tian, Xiaobing Ahsan, Nagib Lulla, Amriti Lev, Avital Abbosh, Philip Dicker, David T Zhang, Shengliang El-Deiry, Wafik S Journal Article United States Neoplasia. 2021 Feb 11;23(3):304-325. doi: 10.1016/j.neo.2021.01.004.