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Cancers 2018, 10(10), 373; https://doi.org/10.3390/cancers10100373

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

1
Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
2
Experimental Tumor Pathology, University Hospital of Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
3
Institute of Pathology, University Hospital of Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
4
Institute of Bioinformatics & Applied Biotechnology (IBAB), Bangalore 560100, India
5
Department of Biochemistry and Microbiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
6
Department of Pathology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre 90050-170, Brazil
*
Authors to whom correspondence should be addressed.
These authors contributed equally as first authors.
These authors contributed equally as corresponding authors.
Received: 23 September 2018 / Revised: 28 September 2018 / Accepted: 2 October 2018 / Published: 9 October 2018
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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. View Full-Text
Keywords: 5-fluorouracil resistance; p21; cytoplasmic p21; Chk2; colorectal cancer; protein interaction 5-fluorouracil resistance; p21; cytoplasmic p21; Chk2; colorectal cancer; protein interaction
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Maiuthed, A.; Ninsontia, C.; Erlenbach-Wuensch, K.; Ndreshkjana, B.; Muenzner, J.K.; Caliskan, A.; Ahmed P., H.; Chaotham, C.; Hartmann, A.; Vial Roehe, A.; Mahadevan, V.; Chanvorachote, P.; Schneider-Stock, R. Cytoplasmic p21 Mediates 5-Fluorouracil Resistance by Inhibiting Pro-Apoptotic Chk2. Cancers 2018, 10, 373.

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