Induction of p53-Dependent Apoptosis by Prostaglandin [A.sub.2]

• Published in: Biomolecules (Basel, Switzerland) Switzerland), 2020-03, Vol.10 (3), p.1
• Main Authors: Lee, Su-Been, Lee, Sangsun, Park, Ji-Young, Lee, Sun-Young, Kim, Ho-Shik
• Format: Article
• Language: English
• Subjects: Apoptosis; Health aspects; Observations; Prostaglandins
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom10030492

Prostaglandin (PG) [A.sub.2], one of cyclopentenone PGs, is known to induce activation of apoptosis in various cancer cells. Although PG[A.sub.2] 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 PG[A.sub.2]-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 PG[A.sub.2] 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 PG[A.sub.2]-treated cells was almost completely prevented by pretreatment with a pan-caspase inhibitor, z-VAD-Fmk, or an inhibitor of protein synthesis, cycloheximide. While PG[A.sub.2] induced apoptosis in HCT116 cells, phosphorylation of p53 and transcriptional induction of p53-target genes such as p[21.sup.WAF1], PUMA, BAX, NOXA, and DR5 occurred. Besides, pretreatment of pifithrin-[alpha] (PFT-[alpha]), a chemical inhibitor of p53's transcriptional activity, interfered with the induction of apoptosis in PG[A.sub.2]-treated HCT116 cells. Pretreatment of NU7441, a small molecule inhibitor of DNA-activated protein kinase (DNA-PK) suppressed PG[A.sub.2]-induced phosphorylation of p53 and apoptosis as well. Moreover, among target genes of p53, knockdown of DR5 expression by RNA interference, suppressed PG[A.sub.2]-induced apoptosis. In the meanwhile, in HCT116 p53-/- cells, PG[A.sub.2] induced apoptosis in delayed time points and with less potency. Delayed apoptosis by PG[A.sub.2] in HCT116 p53-/- cells was also associated with phosphorylation of H2AX but was not inhibited by either PFT-[alpha] or NU7441. Collectively, these results suggest the following. PG[A.sub.2] 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, PG[A.sub.2] may induce apoptosis in a fashion of less potency, which is independent of p53 and DNA-PK in HCT116 p53-/- cells