Inhibition of Polyamine Biosynthesis Reverses Ca2+ Channel Remodeling in Colon Cancer Cells

Autor: Lucía Gutiérrez, Lucía Núñez, Miriam Hernández-Morales, Carlos Villalobos
Přispěvatelé: Universidad de Valladolid, Ministerio de Economía y Competitividad (España), Junta de Castilla y León, Hernández-Morales, Miriam [0000-0001-6487-1735], Villalobos, Carlos [0000-0002-0429-3846], Hernández-Morales, Miriam, Villalobos, Carlos
Rok vydání: 2019
Předmět:
Zdroj: Digital.CSIC. Repositorio Institucional del CSIC
instname
UVaDOC. Repositorio Documental de la Universidad de Valladolid
Cancers
Volume 11
Issue 1
Cancers, Vol 11, Iss 1, p 83 (2019)
ISSN: 2072-6694
Popis: This article belongs to the Special Issue Ion Channels in Cancer.
Store-operated Ca2+ entry (SOCE) is the most important Ca2+ entry pathway in non-excitable cells. Colorectal cancer (CRC) shows decreased Ca2+ store content and enhanced SOCE that correlate with cancer hallmarks and are associated to remodeling of store-operated channels (SOCs). Normal colonic cells display small, Ca2+-selective currents driven by Orai1 channels. In contrast, CRC cells display larger, non-selective currents driven by Orai1 and transient receptor potential canonical type 1 channels (TRPC1). Difluoromethylornithine (DFMO), a suicide inhibitor of ornithine decarboxylase (ODC), the limiting step in polyamine biosynthesis, strongly prevents CRC, particularly when combined with sulindac. We asked whether DFMO may reverse SOC remodeling in CRC. We found that CRC cells overexpress ODC and treatment with DFMO decreases cancer hallmarks including enhanced cell proliferation and apoptosis resistance. Consistently, DFMO enhances Ca2+ store content and decreases SOCE in CRC cells. Moreover, DFMO abolish selectively the TRPC1-dependent component of SOCs characteristic of CRC cells and this effect is reversed by the polyamine putrescine. Combination of DFMO and sulindac inhibit both SOC components and abolish SOCE in CRC cells. Finally, DFMO treatment inhibits expression of TRPC1 and stromal interaction protein 1 (STIM1) in CRC cells. These results suggest that polyamines contribute to Ca2+ channel remodeling in CRC, and DFMO may prevent CRC by reversing channel remodeling.
This research was funded by Ministerio de Economía y Competitividad, Spain, grants BFU2012-37146 and BFU2015-70131R, and Junta de Castilla y León, Spain grant BIO/VA46/14. L.G.G. was supported by a pre-doctoral fellowship from Universidad de Valladolid, Spain.
Databáze: OpenAIRE
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