ERβ is a potent inhibitor of cell proliferation in the HCT8 human colon cancer cell line through regulation of cell cycle components

Abstract

Several strands of evidence indicate that oestrogens exert a protective role against the development of colon cancer through indirect and direct effects on colonic epithelium. Oestrogen receptor b (ERb), the predominant ER subtype in human colon, is significantly decreased in colonic tumours compared with normal mucosa suggesting a potential role in the regulation of colon tumour growth.To investigate this hypothesis we engineered human colon cancer ERa-negative HCT8 cells in order to obtain ERb protein over-expression. Stably transfected cells were cloned and ERb expression and functionality were monitored by RT-PCR, Western blotting and transactivation in an assay using oestrogen-responsive reporter constructs.Over-expression of ERb inhibited cell proliferation and increased cell adhesion in a ligandindependent manner. Its constitutive activation is possibly due to cross-talk with intracellular signalling pathways, as epidermal growth factor and IGF-I were able to induce ERb transactivation.A possible mechanism by which ERb over-expression inhibits proliferation in HCT8 cells is by modulation of some key regulators of the cell cycle; there is a decrease in cyclin E and an increase in the cdk inhibitor p21CIP1. In fact, flow cytometry analysis provided evidence for blocking of the G1-S phase progression induced by ERb over-expression. The magnitude of this effect was affected by the level of ERb expression.These results provide the first direct evidence that ERb plays an important role in colon cancer as a regulator of cell proliferation through the control of key cell cycle modulators and arrest in G1-S phase transition. These findings are compatible with the hypothesis that the loss of ERb expression could be one of the events involved in the development or progression of colon cancer.

Estradiol Alters Cell Growth in Nonmalignant Colonocytes and Reduces the Formation of Preneoplastic Lesions in the Colon

“…Limited data have shown that E 2 treatment reduces cell growth in three colon cancer cell lines, DLD-1, HCT116, and LoVo (25)(26)(27). However, the majority of cell culture studies have shown no reduction or an increase in growth in response to E 2 in colon cancer cells that are fully transformed (13)(14)(15)(16)(17)28).…”

Nitric oxide impairs the 17β-estradiol-induced apoptosis in human colon adenocarcinoma cells

“…By contrast, rapid effects generated by the E2-ERb complex drive cells out of the cell cycle (Acconcia et al 2005a), representing the key to understanding the E2-induced anti-proliferative effects working both during differentiative processes and in some forms of human cancer (e.g. colon adenocarcinoma) (Weihua et al 2003, Bardin et al 2004, Paruthiyil et al 2004, Strom et al 2004, Martineti et al 2005, Koehler et al 2005. S-nitrosylation of ERa results in the selective inhibition of DNA binding to specific EREs without affecting non-genomic events in transiently transfected HeLa cells (Marino et al 2001).…”

Activating Transcription Factor 3-mediated Chemo-intervention with Cancer Chemokines in a Noncanonical Pathway under Endoplasmic Reticulum Stress

“…Preventive Exposure to Apigenin Alters Cancer ER Stress-related Genes and Signals-Endotoxin LPS as another ER stress trigger was assessed for its ability to alter eIF2␣ phosphorylation, which is a central biomarker of ER stress-induced translational arrest in HCT-8 and HCT-116 intestinal cancer cells that are frequently used as a model of inflammatory diseases and carcinogenesis (30,31) (Fig. 1, A and B).…”