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Cytoplasmic p21 Mediates 5-Fluorouracil Resistance by Inhibiting Pro-Apoptotic Chk2

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dc.contributor.author Arnatchai Maiuthed
dc.contributor.author Chatchai Chaotham
dc.contributor.other Chulalongkorn University. Faculty of Pharmaceutical Sciences
dc.date.accessioned 2019-06-17T08:43:59Z
dc.date.available 2019-06-17T08:43:59Z
dc.date.issued 2018-10
dc.identifier.citation Cancers, Volume 10, Issue 10 (October 2018) , p.373 en_US
dc.identifier.issn 20726694
dc.identifier.uri http://cuir.car.chula.ac.th/handle/123456789/62130
dc.description.abstract The oncogenic cytoplasmic p21 contributes to cancer aggressiveness and chemotherapeutic failure. However, the molecular mechanisms remain obscure. Here, we show for the first time that cytoplasmic p21 mediates 5-Fluorouracil (5FU) resistance by shuttling p-Chk2 out of the nucleus to protect the tumor cells from its pro-apoptotic functions. We observed that cytoplasmic p21 levels were up-regulated in 5FU-resistant colorectal cancer cells in vitro and the in vivo Chorioallantoic membrane (CAM) model. Kinase array analysis revealed that p-Chk2 is a key target of cytoplasmic p21. Importantly, cytoplasmic form of p21 mediated by p21T145D transfection diminished p-Chk2-mediated activation of E2F1 and apoptosis induction. Co-immunoprecipitation, immunofluorescence, and proximity ligation assay showed that p21 forms a complex with p-Chk2 under 5FU exposure. Using in silico computer modeling, we suggest that the p21/p-Chk2 interaction hindered the nuclear localization signal of p-Chk2, and therefore, the complex is exported out of the nucleus. These findings unravel a novel mechanism regarding an oncogenic role of p21 in regulation of resistance to 5FU-based chemotherapy. We suggest a possible value of cytoplasmic p21 as a prognosis marker and a therapeutic target in colorectal cancer patients. en_US
dc.language.iso en en_US
dc.publisher MDPI AG en_US
dc.relation.uri https://doi.org/10.3390/cancers10100373
dc.relation.uri https://www.mdpi.com/2072-6694/10/10/373
dc.rights © 2018 by the authors. Licensee MDPI, Basel, Switzerland. en_US
dc.title Cytoplasmic p21 Mediates 5-Fluorouracil Resistance by Inhibiting Pro-Apoptotic Chk2 en_US
dc.type Article en_US
dc.email.author Chatchai.C@chula.ac.th
dc.subject.keyword 5-fluorouracil resistance en_US
dc.subject.keyword cytoplasmic en_US
dc.subject.keyword Chk2 en_US
dc.subject.keyword colorectal cancer en_US
dc.subject.keyword protein interaction en_US
dc.identifier.DOI 10.3390/cancers10100373


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