Induction of p53-Dependent Apoptosis by Prostaglandin A2

Abstract

Prostaglandin (PG) A2, one of cyclopentenone PGs, is known to induce activation of apoptosis in various cancer cells. Although PGA2 has been reported to cause activation of apoptosis by altering the expression of apoptosis-related genes, the role of p53, one of the most critical pro-apoptotic genes, on PGA2-induced apoptosis has not been clarified yet. To address this issue, we compared the apoptosis in HCT116 p53 null cells (HCT116 p53-/-) to that in HCT116 cells containing the wild type p53 gene. Cell death induced by PGA2 was associated with phosphorylation of histone H2A variant H2AX (H2AX), activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase 1 in HCT116 cells. Induction of apoptosis in PGA2-treated cells was almost completely prevented by pretreatment with a pan-caspase inhibitor, z-VAD-Fmk, or an inhibitor of protein synthesis, cycloheximide. While PGA2 induced apoptosis in HCT116 cells, phosphorylation of p53 and transcriptional induction of p53-target genes such as p21WAF1, PUMA, BAX, NOXA, and DR5 occurred. Besides, pretreatment of pifithrin-α (PFT-α), a chemical inhibitor of p53’s transcriptional activity, interfered with the induction of apoptosis in PGA2-treated HCT116 cells. Pretreatment of NU7441, a small molecule inhibitor of DNA-activated protein kinase (DNA-PK) suppressed PGA2-induced phosphorylation of p53 and apoptosis as well. Moreover, among target genes of p53, knockdown of DR5 expression by RNA interference, suppressed PGA2-induced apoptosis. In the meanwhile, in HCT116 p53-/- cells, PGA2 induced apoptosis in delayed time points and with less potency. Delayed apoptosis by PGA2 in HCT116 p53-/- cells was also associated with phosphorylation of H2AX but was not inhibited by either PFT-α or NU7441. Collectively, these results suggest the following. PGA2 may induce p53-dependent apoptosis in which DNA-PK activates p53, and DR5, a transcriptional target of p53, plays a pivotal role in HCT116 cells. In contrast to apoptosis in HCT116 cells, PGA2 may induce apoptosis in a fashion of less potency, which is independent of p53 and DNA-PK in HCT116 p53-/- cells

Infection of Galleria mellonella (Lepidoptera) Larvae With the Entomopathogenic Fungus Conidiobolus coronatus (Entomophthorales) Induces Apoptosis of Hemocytes and Affects the Concentration of Eicosanoids in the Hemolymph

“…Cyclopentenone prostaglandins such as PGA1 and PGA2 have been found to inactivate p53-dependent transcription and induce p53-independent apoptotic cell death ( Lee et al, 2020 ). More specifically, PGA1 appears to induce apoptosis in mammalian cells by specifically binding to H- and N-Ras on endomembranes and activating them ( Anta et al, 2016 ).…”

Induction of DR5-Dependent Apoptosis by PGA2 through ATF4-CHOP Pathway

“…In a previous report, PGA 2 was shown to induce apoptosis dependent on DR5, whose expression was stimulated by DNA-dependent protein kinase (DNA-PK)-p53 pathway in HCT116 cells [16]. However, we also observed that PGA 2 induced apoptosis in HCT116 p53 null cells (HCT116 p53 −/−).…”

Untargeted metabolomics profiling in a mouse model of lung cancer treated with thermal ablation

“…Steroids, such as prostaglandin A2 (PGA2) and prostaglandin J2 (PGJ20), were overexpressed after hyperthermal ablation. Some researchers have reported that PGA2 might induce apoptosis in cancer cells via activation of tumor suppressor protein 53, which is one of the most crucial tumor suppressor genes [ 38 ]. The A and J series of prostaglandins are both characterized by reactive alpha, beta-unsaturated carbonyl compounds, which might be critical for the control of DNA-binding activity [ 39 ].…”