Nonpeptide hormones, such as thyroid hormone, dihydrotestosterone, and estrogen, have been shown to stimulate cancer proliferation via different mechanisms. Aside from their cytosolic or membrane-bound receptors, there are receptors on integrin α β for nonpeptide hormones. Interaction between hormones and integrin α β can induce signal transduction and eventually stimulate cancer cell proliferation. Resveratrol induces inducible COX-2-dependent antiproliferation via integrin α β . Resveratrol and hormone-induced signals are both transduced by activated extracellular-regulated kinases 1 and 2 (ERK1/2); however, hormones promote cell proliferation, while resveratrol induces antiproliferation in cancer cells. Hormones inhibit resveratrol-stimulated phosphorylation of p53 on Ser15, resveratrol-induced nuclear COX-2 accumulation, and formation of p53-COX-2 nuclear complexes. Subsequently, hormones impair resveratrol-induced COX-2-/p53-dependent gene expression. The inhibitory effects of hormones on resveratrol action can be blocked by different antagonists of specific nonpeptide hormone receptors but not integrin α β blockers. Results suggest that nonpeptide hormones inhibit resveratrol-induced antiproliferation in cancer cells downstream of the interaction between ligand and receptor and ERK1/2 activation to interfere with nuclear COX-2 accumulation. Thus, the surface receptor sites for resveratrol and nonpeptide hormones are distinct and can induce discrete ERK1/2-dependent downstream antiproliferation biological activities. It also indicates the complex pathways by which antiproliferation is induced by resveratrol in various physiological hormonal environments. .
The ubiquitin-selective chaperone Cdc48, a member of the AAA (ATPase Associated with various cellular Activities) ATPase superfamily, is involved in many processes, including endoplasmic reticulum-associated degradation (ERAD), ubiquitin- and proteasome-mediated protein degradation, and mitosis. Although Cdc48 was originally isolated as a cell cycle mutant in the budding yeast Saccharomyces cerevisiae, its cell cycle functions have not been well appreciated. We found that temperature-sensitive cdc48-3 mutant is largely arrested at mitosis at 37°C, whereas the mutant is also delayed in G1 progression at 38.5°C. Reporter assays show that the promoter activity of G1 cyclin CLN1, but not CLN2, is reduced in cdc48-3 at 38.5°C. The cofactor npl4-1 and ufd1-2 mutants also exhibit G1 delay and reduced CLN1 promoter activity at 38.5°C, suggesting that Npl4-Ufd1 complex mediates the function of Cdc48 at G1. The G1 delay of cdc48-3 at 38.5°C is a consequence of cell wall defect that over-activates Mpk1, a MAPK family member important for cell wall integrity in response to stress conditions including heat shock. cdc48-3 is hypersensitive to cell wall perturbing agents and is synthetic-sick with mutations in the cell wall integrity signaling pathway. Our results suggest that the cell wall defect in cdc48-3 is exacerbated by heat shock, which sustains Mpk1 activity to block G1 progression. Thus, Cdc48-Npl4-Ufd1 is important for the maintenance of cell wall integrity in order for normal cell growth and division.
Backgrounds: Being a crucial hormone regulating growth, metabolism and various physiological processes, the status of thyroid hormone has long been implicated in cancer risks and tumor developments. In the present study, we aimed to look at the role of thyroid hormone, thyroxine (T4), in colorectal cancer cell proliferation and β-catenin activation, which is highly involved in both normal and oncogenic developments of the gut. Materials and Methods: The effects of T4 in colorectal cancer cell lines HCT 116 (APC wild type) and HT-29 (APC mutant) as well as the primary cells derived from colorectal cancer patients were studied. Cell proliferation was evaluated according to cell counting, MTT assay and qRT-PCR. The activation of β-catenin was examined using Western blotting, qRT-PCR and immunoprecipitation. Results: The results showed that T4 increased the cell number of both HCT 116 and HT-29 cells compared to the untreated cells. In both cell lines, T4 induced nuclear β-catenin accumulation and the protein levels of WNT/β-catenin targets Cyclin D1 and c-Myc. The mRNA expression of CTNNB1 was elevated by T4 in HCT 116 cells, but not in HT-29 cells. In APC wild type HCT 116 cells, T4 increased the WNT4 mRNA expression and decreased the association between β-catenin and the WNT-regulated β-catenin destruction complex. Moreover, the cell numbers of T4-treated primary cells were higher compared to the untreated cells while the mRNA expressions of proliferative genes PCNA, CCND1 and c-Myc were elevated by T4. In the primary cells, T4-induced nuclear β-catenin accumulation, protein levels of Cyclin D1 and c-Myc, and mRNA expressions of CTNNB1 and WNT4 were also observed. Conclusions: T4 promoted cell proliferation and β-catenin activation in colorectal cancer. In the cells with different APC mutation status, the activation of β-catenin was regulated by different mechanisms. Citation Format: Yee-Shin Lee, Meng-Ti Hsieh, Yu-Tang Chin, Aleck Hercbergs, Paul J. Davis, Han-Chung Wu, Hung-Yun Lin. Thyroid hormone, thyroxine, promotes cell proliferation and β-catenin activation in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3625. doi:10.1158/1538-7445.AM2017-3625
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