title: A novel pyrido-thieno-pyrimidine derivative activates p53 through induction of phosphorylation and acetylation in colorectal cancer cells.
abstract: The tumor suppressor p53 plays a key role in regulation of the cell cycle, apoptosis and senescence in response to various stresses. We screened a library of 7920 chemical compounds for the p53 activator and identified N-[2-(dimethylamino)ethyl]-2,3-dimethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-9-carboxamide (PTP), which significantly increased p53-mediated reporter activity in colorectal cancer cells. PTP was found to induce p53 protein and activated transcription of downstream genes, such as p21 and PUMA, in HCT116 cells, leading to growth delay, G1-phase cell cycle arrest, cell senescence and cell death. Proximity ligation assay revealed that PTP weakened the interaction between p53 and murine double minute 2 (MDM2) in situ, thereby inhibiting MDM2-mediated p53 degradation. Although DNA damage has been known to promote phosphorylation of p53 and MDM2, thereby preventing their interaction and stabilizing p53, PTP did not cause DNA damage or activate any DNA damage response signaling. Instead, phosphorylation of p53 was mediated by Erk1/2 MAP kinase. In addition, PTP induced acetylation of p53 at Lys382 in a p300-dependent manner, but sirtuin (SIRT)1 and histone deacetylase (HDAC)1, a well-known p53-regulating deacetylase, were not involved. In the present study, the novel anticancer agent PTP was shown to cause the accumulation of p53 by inducing multiple post-translational modifications, as well as cell cycle arrest, senescence and cell death.
authors.affiliation: Research Center for Radiotherapy, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
authors.forename: Mi Ae
authors.initials: MA
authors.lastname: Kang
authors.affiliation: Research Center for Radiotherapy, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
authors.forename: Mi-Sook
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Research Center for Radiotherapy, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Radiation Oncology, Inje University Sanggye Paik Hospital, Seoul, Republic of Korea.
authors.forename: Young-Joo
authors.initials: YJ
authors.lastname: Shin
authors.affiliation: Research Center for Radiotherapy, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
authors.forename: Jie-Young
authors.initials: JY
authors.lastname: Song
authors.affiliation: Research Center for Radiotherapy, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Jeong
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000819:agonists* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C000600162:N-(2-(dimethylamino)ethyl)-2,3-dimethyl-4-oxo-4H-pyrido(1,2-a)thieno(2,3-d)pyrimidine-9-carboxamide; D011743:Pyrimidines; D011744:Pyrimidinones; C495901:TP53 protein, human; D013876:Thiophenes; D016159:Tumor Suppressor Protein p53