Restoration of the p53 pathway has been a long-term goal in the field of cancer research to treat tumors with mutated p53 and aggressive clinical behavior. p53 pathway restoration in p53-deficient cancers can be achieved by small molecules via p53-dependent or p53-independent processes. Hereafter p53-independent restoration of p53-pathway-signaling in p53-deficient/mutated tumors is referred to as 'restoration of the p53 pathway'. We compare activation of p53 target genes by novel compounds PG3 and PG3-Oc, that activate p53-target genes in a p53-independent manner, and four mutant p53-activating compounds while Nutlin-3a is used as negative control. 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 integrated stress response (ISR) independent of p53. Mutant p53-targeting compounds induce expression of the 3 major downstream p53 target genes and ATF4 in a highly variable and cell-type-dependent manner. PG3 treatment activates ATF4 through ISR via kinase HRI (Heme-Regulated Inhibitor). ATF4 mediates upregulation of PUMA, p21, and NAG-1/GDF15 (Nonsteroidal anti-inflammatory drug-activated gene 1). We note that PUMA mediates apoptosis through activation of caspase-8 in HT29 cells and potentially caspase-10 in SW480 cells. We provide a novel mechanism engaged by PG3 to induce cell death via the HRI/ATF4/PUMA axis. Our results provide unique insights into the mechanism of action of PG3 as a novel cancer therapeutic targeting p53 pathway-like tumor suppression.