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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 | Difusion-weighted magnetic resonance imaging in superior sagittal sinus thrombosis显示文摘 | Wasay M Bakshi R Bobustuc G | 2002 | J Neuroimaging2002，12，3： | 1 |
| 3 | Cerebral venous thrombosis:analysis of a multicenter cohort from the United States显示文摘 | Wasay M Bakshi R Bobustuc G | 2008 | J Stroke Cerebrovasc Dis2008，17，2： | 1 |
| 4 | Cerebral venous thrombosis:analysis of a multicenter cohort from the United States显示文摘 | Wasay M Bakshi R Bobustuc G | | 0，，： | 1 |
| 5 | Local Gene Transduction of Cyclooxygenase-1 Increases Blood Flow in Injured Atherosclerotic Rabbit Arteries显示文摘 | Liu Q Chen ZQ Bobustuc GC | 2005 | Circulation2005，111，14： | 1 |
| 6 | Headache in cerebral venous thrombosis: incidence, pattern and location in 200 consecutive patients显示文摘 | Mohammad Wasay Suleman Kojan Alper I. Dai George Bobustuc Zubair Sheikh | 2010 | The Journal of Headache and Pain2010，，2： | 1 |
| 7 | Cerebral venous thrombosis:analysis of a multicenter cohort from the United States显示文摘 | Wasay M Bakshi R Bobustuc G | 2008 | J StrokeCerebrovasc Dis2008，17，2： | 1 |
| 8 | Diffusion-weighted magnetic resonance imaging in superior sagittal sinus thrombosis显示文摘 | Wasay M Bakshi R Bobustuc G | 2002 | J Neuroimaging2002，12，3： | 1 |
| 9 | Blockade of MGMT expres- sion by 06 benzyl guanine leads to inhibition of pancreatic cancer growth and induction of apoptosis显示文摘 | Konduri SD Ticku J Bobustuc GC et a/ | 2009 | Clin Cancer Res2009，15，19： | 1 |
| 10 | Cerebral venous thrombosis:analysis of a multicenter cohort from the United States显示文摘 | Wasay M Bakshi R Bobustuc G | | 0，，02： | 1 |
| 11 | Cerebral venous thrombosis: analysis of a muhicenter cohort from the United States 显示文摘 | Wasay M Bakshi R Bobustuc G | 2008 | J Stroke Cerebrovasc Dis2008，17，： | 1 |
| 12 | Cerebral venous thrombosis: analysis of a multicenter cohort from the United States 显示文摘 | Wasay M Bakshi R Bobustuc G | 2008 | J Stroke Cerebrovasc Dis2008，17，2： | 1 |
| 13 | MGMT inhibition restores ERa functional sensitivity to antiestrogen therapy显示文摘 | Bobustuc GC Smith JS Maddipatla S | 2012 | Mol Med2012，18，8： | 1 |
| 14 | Diffusion weighted mag netic resonance imaging in superior sagittal sinus thrombosis 显示文摘 | Wasay M Bakshi R Bobustuc G | 2002 | J Neuroimaging2002，12，： | 1 |
| 15 | Cerebral venous thrombosis:analysis of a multicenter cohort from the United States显示文摘 | Wasay M Bakshi R Bobustuc G | 2008 | J Stroke Cerebrovasc Dis2008，17，2： | 1 |
| 16 | Levetiracetam enhances p53-mediated MGMT inhibition and sensitizes glioblastoma cells to temozolomide显示文摘 | Bobustuc GC Baker CH Limaye A | 2010 | Neuro Oncol2010，12，： | 1 |
| 17 | Cerebral venous thrombosis:analysis of a multicenter cohort from the United States显示文摘 | Wasay M Bakshi R Bobustuc G | | 0，，： | 1 |
| 18 | Cerebral venous thrombosis : analysis of a multicenter cohort from the United States显示文摘 | Wasay M Bakshi R Bobustuc G | 2008 | J Stroke Cerebrovasc Dis2008，17，： | 1 |
| 19 | Cere- bral venous thrombosis: analysis of a multicenter cohort from the United States 显示文摘 | Wasay M Bakshi R Bobustuc G | 2008 | J Stroke Cerebrovasc Dis2008，17，： | 1 |
| 20 | Cerebral venous thrombosis:analysis of a multicenter cohort from the United States显示文摘 | Wasay M Bakshi R Bobustuc G | 2008 | J Stroke cerebrovasc Dis2008，17，： | 1 |
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