Abstract
CacyBP/SIP is a component of the ubiquitin pathway and is overexpressed in several transformed tumor tissues, including colon cancer, which is one of the most common cancers worldwide. It is unknown whether CacyBP/SIP promotes the proliferation of colon cancer cells. This study examined the expression level, subcellular localization, and binding activity of CacyBP/SIP in human colon cancer cells in the presence and absence of the hormone gastrin. We found that CacyBP/SIP was expressed in a high percentage of colon cancer cells, but not in normal colonic surface epithelium. CacyBP/SIP promoted the cell proliferation of colon cancer cells under both basal and gastrin stimulated conditions as shown by knockdown studies. Gastrin stimulation triggered the translocation of CacyBP/SIP to the nucleus, and enhanced interaction between CacyBP/SIP and SKP1, a key component of ubiquitination pathway which further mediated the proteasome-dependent degradation of p27kip1 protein. The gastrin induced reduction in p27kip1 was prevented when cells were treated with the proteasome inhibitor MG132. These results suggest that CacyBP/SIP may be promoting growth of colon cancer cells by enhancing ubiquitin-mediated degradation of p27kip1.
Highlights
Colon cancer is one of the most common cancers in the world, and one of the leading causes of death
Calcyclin-binding protein (CacyBP)/Siah-1 Interacting Protein (SIP) protein was expressed in two of the three tested colon cancer cell lines HT29 and SW480 (Fig 1D). These results suggest that CacyBP/SIP overexpression may positively correlate with colon cancer
We showed that CacyBP/SIP is expressed at high levels in several cancers, including colon cancer
Summary
Colon cancer is one of the most common cancers in the world, and one of the leading causes of death. The etiology of colon cancer is multifactorial and has remained poorly defined [1, 2]. Calcyclin-binding protein (CacyBP) interacts with S100A6 (calcyclin) at a physiological range of Ca2+ concentrations in Ehrlich ascites tumor cells [3]. Further investigation demonstrated that the Siah-1 Interacting Protein (SIP) is an ortholog of human CacyBP [4], leading SIP to be renamed as CacyBP/SIP. CacyBP/SIP plays important roles in cellular processes such as ubiquitination, proliferation, differentiation, tumorigenesis, cytoskeletal rearrangement and regulation of transcription [5,6,7,8]. Two research groups reported that CacyBP/SIP was translocated to the nucleus and phosphorylated when intracellular Ca2+ levels are elevated by KCl
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