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

Maiuthed A, Ninsontia C, Erlenbach-Wuensch K, Ndreshkjana B, Muenzner JK, Caliskan A, Ahmed HP, Chaotham C, Hartmann A, Roehe AV, Mahadevan V, Chanvorachote P, Schneider-Stock R (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Cancers MDPI

Book Volume: 10

Journal Issue: 10

DOI: 10.3390/cancers10100373

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.

Authors with CRIS profile

Benardina Ndreshkjana Professur für Experimentelle Tumorpathologie Arndt Hartmann Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie Regine Schneider-Stock Professur für Experimentelle Tumorpathologie

Involved external institutions

Chulalongkorn University / จุฬาลงกรณ์มหาวิทยาลัย TH Thailand (TH) Institute of Bioinformatics and Applied Biotechnology (IBAB) IN India (IN) Universidade Federal de Ciências da Saúde de Porto Alegre BR Brazil (BR)

How to cite

APA:

Maiuthed, A., Ninsontia, C., Erlenbach-Wuensch, K., Ndreshkjana, B., Muenzner, J.K., Caliskan, A.,... Schneider-Stock, R. (2018). Cytoplasmic p21 Mediates 5-Fluorouracil Resistance by Inhibiting Pro-Apoptotic Chk2. Cancers, 10(10). https://doi.org/10.3390/cancers10100373

MLA:

Maiuthed, Arnatchai, et al. "Cytoplasmic p21 Mediates 5-Fluorouracil Resistance by Inhibiting Pro-Apoptotic Chk2." Cancers 10.10 (2018).

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