4.6

CiteScore

2.2

Impact Factor
  • ISSN 1674-8301
  • CN 32-1810/R
Ameya Paranjpe, Nathan I. Bailey, Santhi Konduri, George C. Bobustuc, Francis Ali-Osman, Mohd. A. Yusuf, Surendra R. Punganuru, Hanumantha Rao Madala, Debasish Basak, AGM Mostofa, Kalkunte S. Srivenugopal. New insights into estrogenic regulation of O6-methylguanine DNA-methyltransferase (MGMT) in human breast cancer cells: Co-degradation of ER-α and MGMT proteins by fulvestrant or O6-benzylguanine indicates fresh avenues for therapy[J]. The Journal of Biomedical Research, 2016, 30(5): 393-410. DOI: 10.7555/JBR.30.20160040
Citation: Ameya Paranjpe, Nathan I. Bailey, Santhi Konduri, George C. Bobustuc, Francis Ali-Osman, Mohd. A. Yusuf, Surendra R. Punganuru, Hanumantha Rao Madala, Debasish Basak, AGM Mostofa, Kalkunte S. Srivenugopal. New insights into estrogenic regulation of O6-methylguanine DNA-methyltransferase (MGMT) in human breast cancer cells: Co-degradation of ER-α and MGMT proteins by fulvestrant or O6-benzylguanine indicates fresh avenues for therapy[J]. The Journal of Biomedical Research, 2016, 30(5): 393-410. DOI: 10.7555/JBR.30.20160040

New insights into estrogenic regulation of O6-methylguanine DNA-methyltransferase (MGMT) in human breast cancer cells: Co-degradation of ER-α and MGMT proteins by fulvestrant or O6-benzylguanine indicates fresh avenues for therapy

Funds: 

This work was supported by grants from the Cancer

More Information
  • Received Date: April 01, 2016
  • Revised Date: April 09, 2016
  • Endocrine therapy using estrogen receptor-α (ER-α) antagonists for attenuating horm2one-driven cell proliferation is a major treatment modality for breast cancers. To exploit any DNA repair deficiencies associated with endocrine therapy, we investigated the functional and physical interactions of ER-α with O6-methylguanine DNA methyltransferase (MGMT), a unique DNA repair protein that confers tumor resistance to various anticancer alkylating agents. The ER-α -positive breast cancer cell lines (MCF-7, T47D) and ER- negative cell lines (MDAMB-468, MDAMB-231), and established inhibitors of ER-α and MGMT, namely, ICI-182,780 (Faslodex) and O6-benzylguanine, respectively, were used to study MGMT- ER interactions. The MGMT gene promoter was found to harbor one full and two half estrogen-responsive elements (EREs) and two antioxidant-responsive elements (AREs). MGMT expression was upregulated by estrogen, downregulated by tamoxifen in Western blot and promoter-linked reporter assays. Similarly, both transient and stable transfections of Nrf-2 (nuclear factor-erythroid 2-related factor-2) increased the levels of MGMT protein and activity 3 to 4-fold reflecting novel regulatory nodes for this drug-resistance determinant. Of the different ER-α antagonists tested, the pure anti-estrogen fulvestrant was most potent in inhibiting the MGMT activity in a dose, time and ER-α dependent manner, similar to O6-benzylguanine. Interestingly, fulvestrant exposure led to a degradation of both ER-α and MGMT proteins and O6-benzylguanine also induced a specific loss of ER-α and MGMT proteins in MCF-7 and T47D breast cancer cells with similar kinetics. Immunoprecipitation revealed a specific association of ER-α and MGMT proteins in breast cancer cells. Furthermore, silencing of MGMT gene expression triggered a decrease in the levels of both MGMT and ER-α proteins. The involvement of proteasome in the drug-induced degradation of both proteins was also demonstrated. Fulvestrant enhanced the cytotoxicity of MGMT-targeted alkylating agents, namely, temozolomide and BCNU by 3 to 4-fold in ER-α positive cells, but not in ER–negative cells. We conclude that MGMT and ER-α proteins exist as a complex and are co-targeted for ubiquitin-conjugation and subsequent proteasomal degradation. The findings offer a clear rationale for combining alkylating agents with endocrine therapy.
  • Related Articles

    [1]Izzatullo Ziyoyiddin o`g`li Abdullaev, Ulugbek Gapparjanovich Gayibov, Sirojiddin Zoirovich Omonturdiev, Sobirova Fotima Azamjonovna, Sabina Narimanovna Gayibova, Takhir Fatikhovich Aripov. Molecular pathways in cardiovascular disease under hypoxia: Mechanisms, biomarkers, and therapeutic targets[J]. The Journal of Biomedical Research. DOI: 10.7555/JBR.38.20240387
    [2]Wang Siwan, Jiang Hui, Wang Jia, Wu Haisi, Wu Ting, Ni Mengnan, Zhao Qianqian, Ji You, Zhang Ziting, Tang Chunming, Xu Huae. Superior in vitro anticancer effect of biomimetic paclitaxel and triptolide co-delivery system in gastric cancer[J]. The Journal of Biomedical Research, 2021, 35(4): 327-338. DOI: 10.7555/JBR.35.20210102
    [3]Huanqiang Wang, Congying Yang, Siyuan Wang, Tian Wang, Jingling Han, Kai Wei, Fucun Liu, Jida Xu, Xianzhen Peng, Jianming Wang. Cell-free plasma hypermethylated CASZ1, CDH13 and ING2 are promising biomarkers of esophageal cancer[J]. The Journal of Biomedical Research, 2018, 32(6): 424-433. DOI: 10.7555/JBR.32.20170065
    [4]Ahmad R. Safa, Mohammad Reza Saadatzadeh, Aaron A. Cohen-Gadol, Karen E. Pollok, Khadijeh Bijangi-Vishehsaraei. Emerging targets for glioblastoma stem cell therapy[J]. The Journal of Biomedical Research, 2016, 30(1): 19-31. DOI: 10.7555/JBR.30.20150100
    [5]Lintao Wang, Yanyan Peng, Kaikai Shi, Haixiao Wang, Jianlei Lu, Yanli Li, Changyan Ma. Osthole inhibits proliferation of human breast cancer cells by inducing cell cycle arrest and apoptosis[J]. The Journal of Biomedical Research, 2015, 29(2): 132-138. DOI: 10.7555/JBR.27.20120115
    [6]Di Liu, Peng Xia, Dongmei Diao, Yao Cheng, Hao Zhang, Dawei Yuan, Chen Huang, Chengxue Dang. MiRNA-429 suppresses the growth of gastric cancer cells in vitro[J]. The Journal of Biomedical Research, 2012, 26(5): 389-393. DOI: 10.7555/JBR.26.20120029
    [7]Tian Tian, Yajie Zhang, Shouyu Wang, Jianwei Zhou, Shan Xua. Sox2 enhances the tumorigenicity and chemoresistance of cancer stem-like cells derived from gastric cancer[J]. The Journal of Biomedical Research, 2012, 26(5): 336-345. DOI: 10.7555/JBR.26.20120045
    [8]Xiaoyan Wang, Guozhu Wang, Yi Zhao, Xiaoan Liu, Qiang Ding, Jingping Shi, Yin Ding, Shui Wang. STAT3 mediates resistance of CD44+CD24-/low breast cancer stem cells to tamoxifen in vitro[J]. The Journal of Biomedical Research, 2012, 26(5): 325-335. DOI: 10.7555/JBR.26.20110050
    [9]Bo Cui, Stewart P. Johnson, Nancy Bullock, Francis Ali-Osman, Darell D. Bigner, Henry S. Friedman. Decoupling of DNA damage response signaling from DNA damages underlies temozolomide resistance in glioblastoma cells[J]. The Journal of Biomedical Research, 2010, 24(6): 424-435. DOI: 10.1016/S1674-8301(10)60057-7
    [10]Guixia?Tang, Minjun?Ji, Haiwei?Wu, Guanling?Wu. Antigen?presenting?cells?may?be?able?to?distinguish?between?normal?and?radiated?Schistosoma?japonicum?cercaria:?an?in?vitro?observation[J]. The Journal of Biomedical Research, 2010, 24(4): 285-291. DOI: 10.1016/S1674-8301(10)60040-1
  • Cited by

    Periodical cited type(1)

    1. Gawel AM, Betkowska A, Gajda E, et al. Current Non-Metal Nanoparticle-Based Therapeutic Approaches for Glioblastoma Treatment. Biomedicines, 2024, 12(8): 1822. DOI:10.3390/biomedicines12081822

    Other cited types(0)

Catalog

    Article Metrics

    Article views (3928) PDF downloads (602) Cited by(1)
    Related

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return