Induction of p53-Dependent Apoptosis by Prostaglandin A<sub>2</sub>
Prostaglandin (PG) A<sub>2</sub>, one of cyclopentenone PGs, is known to induce activation of apoptosis in various cancer cells. Although PGA<sub>2</sub> has been reported to cause activation of apoptosis by altering the expression of apoptosis-related genes, the role of p53,...
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MDPI AG
2020-03-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/10/3/492 |
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| author | Su-Been Lee Sangsun Lee Ji-Young Park Sun-Young Lee Ho-Shik Kim |
| author_facet | Su-Been Lee Sangsun Lee Ji-Young Park Sun-Young Lee Ho-Shik Kim |
| author_sort | Su-Been Lee |
| collection | DOAJ |
| description | Prostaglandin (PG) A<sub>2</sub>, one of cyclopentenone PGs, is known to induce activation of apoptosis in various cancer cells. Although PGA<sub>2</sub> 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 PGA<sub>2</sub>-induced apoptosis has not been clarified yet. To address this issue, we compared the apoptosis in HCT116 <i>p53</i> null cells (HCT116 p53-/-) to that in HCT116 cells containing the wild type <i>p53</i> gene. Cell death induced by PGA<sub>2</sub> 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 PGA<sub>2</sub>-treated cells was almost completely prevented by pretreatment with a pan-caspase inhibitor, z-VAD-Fmk, or an inhibitor of protein synthesis, cycloheximide. While PGA<sub>2</sub> induced apoptosis in HCT116 cells, phosphorylation of p53 and transcriptional induction of p53-target genes such as <i>p21<sup>WAF1</sup></i>, <i>PUMA</i>, <i>BAX</i>, <i>NOXA</i>, and <i>DR5</i> occurred. Besides, pretreatment of pifithrin-α (PFT-α), a chemical inhibitor of p53’s transcriptional activity, interfered with the induction of apoptosis in PGA<sub>2</sub>-treated HCT116 cells. Pretreatment of NU7441, a small molecule inhibitor of DNA-activated protein kinase (DNA-PK) suppressed PGA<sub>2</sub>-induced phosphorylation of p53 and apoptosis as well. Moreover, among target genes of p53, knockdown of <i>DR5</i> expression by RNA interference, suppressed PGA<sub>2</sub>-induced apoptosis. In the meanwhile, in HCT116 p53-/- cells, PGA<sub>2</sub> induced apoptosis in delayed time points and with less potency. Delayed apoptosis by PGA<sub>2</sub> 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. PGA<sub>2</sub> 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, PGA<sub>2</sub> may induce apoptosis in a fashion of less potency, which is independent of p53 and DNA-PK in HCT116 p53-/- cells |
| first_indexed | 2024-12-13T02:56:56Z |
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| language | English |
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| publishDate | 2020-03-01 |
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| spelling | doaj.art-a7be1f96468b422d8541a791d7345fd82022-12-22T00:01:57ZengMDPI AGBiomolecules2218-273X2020-03-0110349210.3390/biom10030492biom10030492Induction of p53-Dependent Apoptosis by Prostaglandin A<sub>2</sub>Su-Been Lee0Sangsun Lee1Ji-Young Park2Sun-Young Lee3Ho-Shik Kim4Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, KoreaDepartment of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, KoreaDepartment of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, KoreaCancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, KoreaDepartment of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, KoreaProstaglandin (PG) A<sub>2</sub>, one of cyclopentenone PGs, is known to induce activation of apoptosis in various cancer cells. Although PGA<sub>2</sub> 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 PGA<sub>2</sub>-induced apoptosis has not been clarified yet. To address this issue, we compared the apoptosis in HCT116 <i>p53</i> null cells (HCT116 p53-/-) to that in HCT116 cells containing the wild type <i>p53</i> gene. Cell death induced by PGA<sub>2</sub> 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 PGA<sub>2</sub>-treated cells was almost completely prevented by pretreatment with a pan-caspase inhibitor, z-VAD-Fmk, or an inhibitor of protein synthesis, cycloheximide. While PGA<sub>2</sub> induced apoptosis in HCT116 cells, phosphorylation of p53 and transcriptional induction of p53-target genes such as <i>p21<sup>WAF1</sup></i>, <i>PUMA</i>, <i>BAX</i>, <i>NOXA</i>, and <i>DR5</i> occurred. Besides, pretreatment of pifithrin-α (PFT-α), a chemical inhibitor of p53’s transcriptional activity, interfered with the induction of apoptosis in PGA<sub>2</sub>-treated HCT116 cells. Pretreatment of NU7441, a small molecule inhibitor of DNA-activated protein kinase (DNA-PK) suppressed PGA<sub>2</sub>-induced phosphorylation of p53 and apoptosis as well. Moreover, among target genes of p53, knockdown of <i>DR5</i> expression by RNA interference, suppressed PGA<sub>2</sub>-induced apoptosis. In the meanwhile, in HCT116 p53-/- cells, PGA<sub>2</sub> induced apoptosis in delayed time points and with less potency. Delayed apoptosis by PGA<sub>2</sub> 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. PGA<sub>2</sub> 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, PGA<sub>2</sub> may induce apoptosis in a fashion of less potency, which is independent of p53 and DNA-PK in HCT116 p53-/- cellshttps://www.mdpi.com/2218-273X/10/3/492apoptosisprostaglandin a<sub>2</sub>tumor suppressor protein p53dna-activated protein kinasedeath receptor |
| spellingShingle | Su-Been Lee Sangsun Lee Ji-Young Park Sun-Young Lee Ho-Shik Kim Induction of p53-Dependent Apoptosis by Prostaglandin A<sub>2</sub> Biomolecules apoptosis prostaglandin a<sub>2</sub> tumor suppressor protein p53 dna-activated protein kinase death receptor |
| title | Induction of p53-Dependent Apoptosis by Prostaglandin A<sub>2</sub> |
| title_full | Induction of p53-Dependent Apoptosis by Prostaglandin A<sub>2</sub> |
| title_fullStr | Induction of p53-Dependent Apoptosis by Prostaglandin A<sub>2</sub> |
| title_full_unstemmed | Induction of p53-Dependent Apoptosis by Prostaglandin A<sub>2</sub> |
| title_short | Induction of p53-Dependent Apoptosis by Prostaglandin A<sub>2</sub> |
| title_sort | induction of p53 dependent apoptosis by prostaglandin a sub 2 sub |
| topic | apoptosis prostaglandin a<sub>2</sub> tumor suppressor protein p53 dna-activated protein kinase death receptor |
| url | https://www.mdpi.com/2218-273X/10/3/492 |
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