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

Lucía Gutiérrez,Lucía Núñez,Carlos Villalobos,Miriam Hernández-Morales

doi:10.3390/cancers11010083

Abstract

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.

Highlights

Colorectal cancer (CRC) is the third most common cancer worldwide and the fourth most common cause of cancer death
CRC is considered a model of choice for cancer chemoprevention studies for two reasons: First, the molecular history of CRC is well established and involves early mutations in the adenomatous polyposis coli (APC) gene linked to hyperplasia followed by mutations in oncogenes and tumor repressors as in c-myc, K-ras, and p53 that lead to adenoma, adenocarcinoma, and carcinoma [2]
In likely contributing to sustained signaling in cancer cells. We report that this transient receptor potential channel 1 (TRPC1)-dependent addition, this possibility is supported by a previous report showing that polyamines may component observed only in CRC cells is selectively removed by2+treatment with DFMO and this regulate intestinal epithelial restitution through TRPC1-mediated Ca signaling by altering the ratio effectofisSTIM1 fully reversed an excess of epithelial polyamine putrescine indicating that

Summary

Introduction

Colorectal cancer (CRC) is the third most common cancer worldwide and the fourth most common cause of cancer death. There are about 1,250,000 new CRC cases and more than 600,000 related deaths every year [1]. CRC is considered a model of choice for cancer chemoprevention studies for two reasons: First, the molecular history of CRC is well established and involves early mutations in the adenomatous polyposis coli (APC) gene linked to hyperplasia followed by mutations in oncogenes and tumor repressors as in c-myc, K-ras, and p53 that lead to adenoma, adenocarcinoma, and carcinoma [2]. CRC chemoprevention studies using cell lines, animal models, and even clinical trials which have provided multiple candidate compounds for chemoprevention. In top of most lists of cancer chemoprevention compounds is Difluoromethylornithine (DFMO), named eflornithine [3,4]

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