Cyclooxygenase-2 induces neoplastic transformation by inhibiting p53-dependent oncogene-induced senescence

Abstract Much in vivo evidence indicates that cyclooxygenase-2 (COX-2) is deeply involved in tumorigenesis. Although it has been proposed that COX-2-derived pro-inflammatory prostanoids mediate the tumorigenic activity of COX-2, the tumorigenic mechanisms of COX-2 are not yet fully understood. Here,...

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Autores principales:	Hyeon Ju Lee, So Ra Kim, Yu-Jin Jung, Jeong A. Han
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e6a376ecfa294707ac3d9a8703eab09e
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spelling	oai:doaj.org-article:e6a376ecfa294707ac3d9a8703eab09e2021-12-02T14:35:53ZCyclooxygenase-2 induces neoplastic transformation by inhibiting p53-dependent oncogene-induced senescence10.1038/s41598-021-89220-52045-2322https://doaj.org/article/e6a376ecfa294707ac3d9a8703eab09e2021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89220-5https://doaj.org/toc/2045-2322Abstract Much in vivo evidence indicates that cyclooxygenase-2 (COX-2) is deeply involved in tumorigenesis. Although it has been proposed that COX-2-derived pro-inflammatory prostanoids mediate the tumorigenic activity of COX-2, the tumorigenic mechanisms of COX-2 are not yet fully understood. Here, we investigated the mechanism by which COX-2 causes transformation from normal cells to malignant cells by using normal murine or human cells. We found that COX-2 inhibits the pro-senescent function of p53 under oncogenic RAS activation, by which it prevents oncogene-induced senescence (OIS) and induces neoplastic transformation. We also found that COX-2 physically interacts with p53 in the nucleus under oncogenic RAS activation, and that this COX-2-p53 interaction rather than the catalytic activity is involved in the COX-2-mediated inhibition of the pro-senescent function of p53 and OIS, and induction of neoplastic transformation. These findings strongly suggest that the oncogenic property of COX-2 is closely related to its ability to inactivate p53 under strong mitogenic signals, and that aberrant activation of the COX-2/a mitogenic oncogene combination can be a potent driving force for tumorigenesis. This study might contribute to our understanding of the molecular basis for the tumorigenic activity of COX-2 and the development of novel anti-tumor drugs targeting COX-2-p53 interactions.Hyeon Ju LeeSo Ra KimYu-Jin JungJeong A. HanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Hyeon Ju Lee So Ra Kim Yu-Jin Jung Jeong A. Han Cyclooxygenase-2 induces neoplastic transformation by inhibiting p53-dependent oncogene-induced senescence
description	Abstract Much in vivo evidence indicates that cyclooxygenase-2 (COX-2) is deeply involved in tumorigenesis. Although it has been proposed that COX-2-derived pro-inflammatory prostanoids mediate the tumorigenic activity of COX-2, the tumorigenic mechanisms of COX-2 are not yet fully understood. Here, we investigated the mechanism by which COX-2 causes transformation from normal cells to malignant cells by using normal murine or human cells. We found that COX-2 inhibits the pro-senescent function of p53 under oncogenic RAS activation, by which it prevents oncogene-induced senescence (OIS) and induces neoplastic transformation. We also found that COX-2 physically interacts with p53 in the nucleus under oncogenic RAS activation, and that this COX-2-p53 interaction rather than the catalytic activity is involved in the COX-2-mediated inhibition of the pro-senescent function of p53 and OIS, and induction of neoplastic transformation. These findings strongly suggest that the oncogenic property of COX-2 is closely related to its ability to inactivate p53 under strong mitogenic signals, and that aberrant activation of the COX-2/a mitogenic oncogene combination can be a potent driving force for tumorigenesis. This study might contribute to our understanding of the molecular basis for the tumorigenic activity of COX-2 and the development of novel anti-tumor drugs targeting COX-2-p53 interactions.
format	article
author	Hyeon Ju Lee So Ra Kim Yu-Jin Jung Jeong A. Han
author_facet	Hyeon Ju Lee So Ra Kim Yu-Jin Jung Jeong A. Han
author_sort	Hyeon Ju Lee
title	Cyclooxygenase-2 induces neoplastic transformation by inhibiting p53-dependent oncogene-induced senescence
title_short	Cyclooxygenase-2 induces neoplastic transformation by inhibiting p53-dependent oncogene-induced senescence
title_full	Cyclooxygenase-2 induces neoplastic transformation by inhibiting p53-dependent oncogene-induced senescence
title_fullStr	Cyclooxygenase-2 induces neoplastic transformation by inhibiting p53-dependent oncogene-induced senescence
title_full_unstemmed	Cyclooxygenase-2 induces neoplastic transformation by inhibiting p53-dependent oncogene-induced senescence
title_sort	cyclooxygenase-2 induces neoplastic transformation by inhibiting p53-dependent oncogene-induced senescence
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/e6a376ecfa294707ac3d9a8703eab09e
work_keys_str_mv	AT hyeonjulee cyclooxygenase2inducesneoplastictransformationbyinhibitingp53dependentoncogeneinducedsenescence AT sorakim cyclooxygenase2inducesneoplastictransformationbyinhibitingp53dependentoncogeneinducedsenescence AT yujinjung cyclooxygenase2inducesneoplastictransformationbyinhibitingp53dependentoncogeneinducedsenescence AT jeongahan cyclooxygenase2inducesneoplastictransformationbyinhibitingp53dependentoncogeneinducedsenescence
_version_	1718391041183186944

Cyclooxygenase-2 induces neoplastic transformation by inhibiting p53-dependent oncogene-induced senescence

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