Please use this identifier to cite or link to this item: https://hdl.handle.net/11147/5275
Title: 5-Fluorouracil signaling through a calcium-calmodulin-dependent pathway is required for p53 activation and apoptosis in colon carcinoma cells
Authors: Can, G.
Akpınar, B.
Baran, Yusuf
Zhivotovsky, B.
Olsson, M.
Baran, Yusuf
Izmir Institute of Technology. Molecular Biology and Genetics
Keywords: Fluorouracil
Apoptosis
Calcium
Calmodulin
Protein p53
Proteins
Issue Date: Sep-2013
Publisher: Nature Publishing Group
Source: Can, G., Akpınar, B., Baran, Y., Zhivotovsky, B., and Olsson, M. (2013). 5-Fluorouracil signaling through a calcium-calmodulin-dependent pathway is required for p53 activation and apoptosis in colon carcinoma cells. Oncogene, 32(38), 4529-4538. doi:10.1038/onc.2012.467
Abstract: 5-Fluorouracil (5-FU) is an anti-metabolite that is in clinical use for treatment of several cancers. In cells, it is converted into three distinct fluoro-based nucleotide analogs, which interfere with DNA synthesis and repair, leading to genome impairment and, eventually, apoptotic cell death. Current knowledge states that in certain cell types, 5-FU-induced stress is signaling through a p53-dependent induction of tumor necrosis factor-receptor oligomerization required for death-inducing signaling complex formation and caspase-8 activation. Here we establish a role of calcium (Ca 2+) as a messenger for p53 activation in response to 5-FU. Using a combination of pharmacological and genetic approaches, we show that treatment of colon carcinoma cells stimulates entry of extracellular Ca 2+ through long lasting-type plasma membrane channels, which further directs posttranslational phosphorylation of at least three p53 serine residues (S15, S33 and S37) by means of calmodulin (CaM) activity. Obstructing this pathway by the Ca 2+ -chelator BAPTA (1,2-bis(o-aminophenoxy)ethane- N,N,N',N'-tetraacetic acid) or by inhibitors of CaM efficiently reduces 5-FU-induced caspase activities and subsequent cell death. Moreover, ectopic expression of p53 S15A in HCT116 p53 -/- cells confirmed the importance of a Ca 2+ -CaM-p53 axis in 5-FU-induced extrinsic apoptosis. The fact that a widely used therapeutic drug, such as 5-FU, is operating via this pathway could provide new therapeutic intervention points, or specify new combinatorial treatment regimes. © 2013 Macmillan Publishers Limited.
URI: http://doi.org/10.1038/onc.2012.467
http://hdl.handle.net/11147/5275
ISSN: 0950-9232
1476-5594
0950-9232
Appears in Collections:Molecular Biology and Genetics / Moleküler Biyoloji ve Genetik
OpenAIRE Collection / OpenAIRE Koleksiyonu
Scopus İndeksli Yayınlar Koleksiyonu / Scopus Indexed Publications Collection
WoS İndeksli Yayınlar Koleksiyonu / WoS Indexed Publications Collection

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