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Over-expressed estrogen receptor-α up-regulates hTNF-α gene expression and down-regulates β-catenin signaling activity to induce the apoptosis and inhibit proliferation of LoVo colon cancer cells

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Abstract

Epidemiologic studies reported that the prevalence of hereditary non-polyposis colon cancer (HNPCC) in male is about 1.5-fold higher than that in female. Decreases in circulatory estrogen (E2) have been reported to downregulate the expression of E2 receptor (ER) and significantly increase the risk of colorectal cancer. Patients that received E2 replacement therapy were found to have a reduction in the incidence of colon adenoma and carcinoma. Furthermore, significant decreases in the expression of ER have been found in colorectal cancer specimens. Evidences strongly suggest the protective roles of E2 and ER against colorectal cancer. However, the mechanisms of ERα effects on colorectal cancer cells remained un-clear. LoVo cells were transient transfected to overexpress ERα, DNA fragmentation and the activated caspases measurements were performed to evaluate apoptotic effects. Western blotting was used to evaluate protein levels, and luciferase activity assay to measure the Htnf-a promoter activity. The results clearly demonstrated that overexpressed ERα with or without E2 (10−8 M) treatment could activate caspase -8, -9, and 3 and induce DNA fragmentation in LoVo cell. At the same time, overexpressed ERα plus E2 significantly increases the expression and promoter activity of hTNF-α, and the DNA fragmentation effect induced by E2 plus ERα were reduced by the addition of hTNF antibody (0.1 ng(ml). In addition, E2 plus ERα significantly upregulated p21 and p27 levels and downregulated the β-catenin and its target genes, cyclin D1 and Rb, which regulate the cell cycle and cell proliferation. The results indicate that E2 plus overexpressed ERα induce LoVo cell apoptosis might mediate through the increase of hTNF-α gene expression, which in turn activate caspase-8, -9 and caspase-3 and lead to the DNA fragmentation and apoptosis. E2 plus ERα also showed the downregulation of β-catenin signalings implicating the suppression of proliferation and metastasis of colorectal cells. Efforts aiming at enhancing ERα expression and(or activity may be proved to be an alternative therapy against colorectal cancer.

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Authors and Affiliations

  1. Division of Colorectal Surgery, Mackay Memorial Hospital, Taipei, Taiwan

    Hsi-Hsien Hsu

  2. Department of Pharmacy, Veterans General Hospital-Taipei, Taipei, Taiwan

    Sue-Fei Cheng

  3. Department of Internal Medicine, Armed Forces Taichung General Hospital Taichung, Taichung, Taiwan, ROC

    Li-Mien Chen

  4. Institute of Biochemistry and Biotechnology, Chung-Shan Medical University, No. 110, Section 1, Chien Kuo N. Rd., Taichung, 402, Taiwan

    Jer-Yu Liu, Chun-Hsien Chu, Yi-Jiun Weng, Zih-Ying Li & Chih-Yang Huang

  5. Department of Internal Medicine, Chung-Shan Hospital, Taichung, Taiwan

    Chung-Sheng Lin

  6. School of Physical Therapy, Chung-Shan Medical University, Taichung, Taiwan

    Shin-Da Lee

  7. Department of Biological Science and Technology, Taichung, Taiwan

    Wei-Wen Kuo

  8. Graduate Institute of Chinese Medical Science, China Medical University, Taichung, Taiwan

    Chih-Yang Huang

  9. Mackay Medicine, Nursingand Management College, Taipei, Taiwan

    Hsi-Hsien Hsu

  10. Institute of Medicine, Chung–Shan Medical University, Taichung, Taiwan

    Hsi-Hsien Hsu

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  1. Hsi-Hsien Hsu
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  2. Sue-Fei Cheng
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  11. Chih-Yang Huang
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Correspondence to Chih-Yang Huang.

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Hsu, HH., Cheng, SF., Chen, LM. et al. Over-expressed estrogen receptor-α up-regulates hTNF-α gene expression and down-regulates β-catenin signaling activity to induce the apoptosis and inhibit proliferation of LoVo colon cancer cells. Mol Cell Biochem 289, 101–109 (2006). https://doi.org/10.1007/s11010-006-9153-3

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  • DOI: https://doi.org/10.1007/s11010-006-9153-3

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