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| 1 | New insights into estrogenic regulation of O^6-methylguanine DNA-methyltransferase (MGMT) in human breast cancer cells: Co-degradation of ER-α and MGMT proteins by fulvestrant or O^6-benzylguanine indicates fresh avenues for therapy显示文摘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 O^6-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 O^6-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 drugresistance 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 O^6-benzylguanine.Interestingly,fulvestrant exposure led to a degradation of both ER-α and MGMT proteins and O^6-benzylguanine also induced a specific loss of ER-α and MGMT proteins in MCF-7 and T47 D 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. | Ameya Paranjpe Nathan I. Bailes Santhi Konduri George C. Bobustuc Francis Ali-Osman Mohd. A. Yusuf Surendra R. Punganuru Hanumantha Rao Madal Debasish Basak AGM Mostofa Kalkunte S. Srivenugopa | 2016 | The Journal of Biomedical Research2016，30，5： | 5 |
| 2 | Decreased association of HSP90 impairs endothelial nitric oxide synthase in fetal lambs with persistent pulmonary hypertension显示文摘 | Konduri GG Ou J Shi Y | 2003 | Am J Physiol Heart Circ Physiol2003，285，1： | 1 |
| 3 | Advances in the diagnosis and management of persistent pulmonary hypertension of the newborn 显示文摘 | Konduri GG Kim UO | 2009 | Pediatr Clin North Am2009，56，3： | 1 |
| 4 | Adenosine infusion improves oxygenation in term infants with respiratory failure显示文摘 | Garcia DC Kazzi NJ | 1996 | Pediatrics1996，97，3： | 1 |
| 5 | Angiogenesis:an update and potential drug approaches (review)显示文摘 | Abdelrahim M Konduri S Basha R | 2010 | Int J Oncol2010，36，1： | 1 |
| 6 | Promoter methylation and silencing of the tissue factor pathway inhibitor-2, a gene encoding an inhibitor of matrix metalloproteinases in human glioma cells显示文摘 | Konduri S D Srivenugopal K S Yanamandra N | 2003 | Oncogene2003，22，29： | 1 |
| 7 | Relationships be- tween hard-seededness and seed weight in mungbean( Vigna radi- ata) assessed by QTL analysis 显示文摘 | Humphry M E Konduri M E V Liu C J | 2005 | Plant Breed2005，124，： | 1 |
| 8 | A novel role of tissue factor pathway inhibitor-2 in apoptosis of malignant human gliomas显示文摘 | Tasiou A Konduri SD Yanamandra N | 2001 | Int J Oncol2001，19，3： | 1 |
| 9 | Estrogen receptor alpha inhibits p53-mediated transcriptional repression:implications for the regulation of apoptosis显示文摘 | Sayeed A Konduri SD Liu W | 2007 | Cancer Res2007，67，16： | 1 |
| 10 | Adenosine in a pulmonary vasodilator in newborn lambs显示文摘 | Woodard LL Mukhopadhyay A | 1992 | Am Rev Respir Dis1992，146，： | 1 |
| 11 | Oxidant stress from uncoupled nitric oxide synthase impairs vasodilation in fetal lambs with persistent pulmonary hypertension 显示文摘 | Konduri GG Bakhutashvili I Eis A el al | 2007 | Am J Physiol Heart Circ Physiol2007，292，4： | 1 |
| 12 | Modulation of cystatin C expression impairs the invasive and tumorigenic potential of human glioblastoma cell显示文摘 | Konduri SD Yanamadra N Siddique K | 2002 | Oncogene2002，21，： | 1 |
| 13 | Promoter methylation and silencing of the tissue factor pathway inhibitor-2, a gene encoding an inhibitor of matrix metalloproteinases in human glioma cells显示文摘 | Konduri SD Srivenugopal KS Yanamandra N | 2003 | Oncogene2003，22，29： | 1 |
| 14 | Early inhaled nitric oxide therapy for term and near - term newborn infants with respiratory failure : neurondevelopmental follow - up 显示文摘 | Konduri GG Vohr B Robertson C | 2007 | Pediatrics2007，150，3： | 1 |
| 15 | In vitro modulation of human lung cancer cell line invasiveness by antisense cDNA of tissue factor pathway inhibitor-2 显示文摘 | Lakka SS Konduri SD Mohanam S | 2000 | Clin Exp Metastasis2000，18，3： | 1 |
| 16 | Role of tissue pathway inhibitor-2(TFPI-2) in amelanotie melanoma(C-32) invasion 显示文摘 | Konduri SD Tasiou A Chandrasekar N | 2000 | Clin Exp Metastasis2000，18，： | 1 |
| 17 | Oxidant stress from uncoupled nitric oxide synthase impairs vasodilation in fetal lambs with persistent pulmonary hypertension显示文摘 | Konduri G G Bakhutashvili I Eis A | 2007 | Am J Physiol Heart Cite Physiol2007，292，4： | 1 |
| 18 | A novel function of tissue factor pathway inhibitor-2(TFPI-2) in human glioma invasion 显示文摘 | Konduri SD Rao CN Chandrasekar N | 2001 | Oncogene2001，20，： | 1 |
| 19 | Androgen Receptor Blockade in Experimental Combination Therapy of Pancreatic Cancer显示文摘 | Srivani Konduri Margaret A. Schwarz Danielle Cafasso Roderich E. Schwarz | 2007 | Journal of Surgical Research2007，，2： | 1 |
| 20 | A novel function of tissue factor pathway inhibitor-2 (TFPI-2) in human glioma invasion显示文摘 | Konduri S D Rao C N Chandrasekar N | 2001 | Oncogene2001，20，47： | 1 |
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