Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, RI, USA; The Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI, USA; Department of Pathology and Laboratory Medicine, Brown University Alpert Medical School, Providence, RI, USA; Division of Biology and Medicine, Brown University, Providence, RI, USA; Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
The Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI, USA; COBRE Center for Cancer Research Development, Proteomics Core Facility, Rhode Island Hospital, Providence, RI, USA; Division of Biology and Medicine, Brown University, Providence, RI, USA.
Neoplasia. 2021 Mar;23(3):304-325. doi: 10.1016/j.neo.2021.01.004. Epub 2021 Feb 11.
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.
长期以来，癌症领域的一个目标是开发治疗 p53 突变肿瘤的策略。一种新型小分子 PG3-Oc 可独立于 p53/p73 恢复具有突变 p53 的肿瘤细胞中的 p53 信号通路。PG3-Oc 部分上调 p53 转录组（公共 p53 靶基因数据集的 13.7%；内部数据集的 15.2%）和 p53 蛋白质组（18%，HT29；16%，HCT116-p53）。生物信息学分析表明，生长抑制（p21）、凋亡（PUMA、DR5、Noxa）、自噬（DRAM1）和转移抑制（NDRG1）的关键 p53 效应物被 PG3-Oc 诱导。ERK1/2 和 CDK9 激酶是 PG3-Oc 上调 ATF4 所必需的，这可以恢复无功能 p53 细胞中的 p53 转录组靶标。PG3-Oc 抑制 MYC（不依赖 ATF4），并在介导细胞死亡时上调 PUMA（依赖 ATF4）。诱导的 ATF4 在药物处理的细胞中恢复 p53 转录组靶标，包括功能重要的介质，如 PUMA 和 DR5，其转录组与 PG3-Oc 有很大的重叠。我们的结果表明，涉及 ERK1/2、CDK9 和 ATF4 的新型 p53 非依赖性药物诱导的分子重编程，可恢复细胞死亡和肿瘤抑制所需的 p53 效应基因的上调。
