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]Vitaly Chasov, Damir Davletshin, Elvina Gilyazova, Regina Mirgayazova, Anna Kudriaeva, Raniya Khadiullina, Youyong Yuan, Emil Bulatov. Anticancer therapeutic strategies for targeting mutant p53-Y220C[J]. The Journal of Biomedical Research, 2024, 38(3): 222-232. DOI: 10.7555/JBR.37.20230093
    [3]Qing Chen, Meiheng Sun, Xu Han, Hongfei Xu, Yongjian Liu. Structural determinants specific for retromer protein sorting nexin 5 in regulating subcellular retrograde membrane trafficking[J]. The Journal of Biomedical Research, 2023, 37(6): 492-506. DOI: 10.7555/JBR.37.20230112
    [4]Minqin Xu, Lihua Zhang, Lan Lin, Zhiyi Qiang, Wei Liu, Jian Yang. Cisplatin increases carboxylesterases through increasing PXR mediated by the decrease of DEC1[J]. The Journal of Biomedical Research, 2023, 37(6): 431-447. DOI: 10.7555/JBR.37.20230047
    [5]Xiaochen Huang, Jiaojiao Guo, Tao Li, Lizhou Jia, Xiaojun Tang, Jin Zhu, Qi Tang, Zhenqing Feng. c-Met-targeted chimeric antigen receptor T cells inhibit hepatocellular carcinoma cells in vitro and in vivo[J]. The Journal of Biomedical Research, 2022, 36(1): 10-21. DOI: 10.7555/JBR.35.20200207
    [6]Adittya Arefin, Tanzila Ismail Ema, Tamnia Islam, Md. Saddam Hossen, Tariqul Islam, Salauddin Al Azad, Md. Nasir Uddin Badal, Md. Aminul Islam, Partha Biswas, Nafee Ul Alam, Enayetul Islam, Maliha Anjum, Afsana Masud, Md. Shaikh Kamran, Ahsab Rahman, Parag Kumar Paul. Target specificity of selective bioactive compounds in blocking α-dystroglycan receptor to suppress Lassa virus infection: an in silico approach[J]. The Journal of Biomedical Research, 2021, 35(6): 459-473. DOI: 10.7555/JBR.35.20210111
    [7]Sun Meihen, Han Xu, Chang Fei, Xu Hongfei, Colgan Lesley, Liu Yongjian. Regulatory role of sorting nexin 5 in protein stability and vesicular targeting of vesicular acetylcholine transporter to synaptic vesicle-like vesicles in PC12 cells[J]. The Journal of Biomedical Research, 2021, 35(5): 339-350. DOI: 10.7555/JBR.34.20200095
    [8]Min Feng, Xin Hu, Na Li, Fan Hu, Fei Chang, Hongfei Xu, Yongjian Liu. Distinctive roles of Rac1 and Rab29 in LRRK2 mediated membrane trafficking and neurite outgrowth[J]. The Journal of Biomedical Research, 2018, 32(2): 145-156. DOI: 10.7555/JBR.31.20170039
    [9]Qiuzi Wu, Hongfei Xu, Wei Wang, Fei Chang, Yu Jiang, Yongjian Liu. Retrograde trafficking of VMAT2 and its role in protein stability in non-neuronal cells[J]. The Journal of Biomedical Research, 2016, 30(6): 502-509. DOI: 10.7555/JBR.30.20160061
    [10]Oluyomi S. Adeyemi, Faoziyat A. Sulaiman. Evaluation of metal nanoparticles for drug delivery systems[J]. The Journal of Biomedical Research, 2015, 29(2): 145-149. DOI: 10.7555/JBR.28.20130096

Catalog

    Article Metrics

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

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return