MGMT Inhibition Restores ERα Functional Sensitivity to Antiestrogen Therapy

Bobustuc, George C.; Smith, Joshua S.; Maddipatla, Sreeram; Jeudy, Sheila; Limaye, Arati; Isley, Beth; Caparas, Maria-Lourdes M; Constantino, Susan M; Shah, Nikita; Baker, Cheryl H.; Srivenugopal, Kalkunte S.; Baidas, Said; Konduri, Santhi D.

doi:10.2119/molmed.2012.00010

Cited by 14 publications

(16 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Aberrant proliferation of PD fibroblasts has also been detected in PD patients (28). To inhibit PD fibroblast proliferation, many agents with anti-fibrotic potential have been employed to downregulate or neutralize proliferative, fibrogenic and contractile responses of myofibroblasts (29). Thus, we first investigated the anti-proliferation effect of HS-173 on PD-derived fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

A novel PI3K inhibitor alleviates fibrotic responses in fibroblasts derived from Peyronie’s plaques

Jung

Ryu

Lee

et al. 2013

International Journal of Oncology

View full text Add to dashboard Cite

Peyronie's disease (PD) is fibrosis localized in the tunica albuginea that is characterized by penile deformity and curvature. The pathogenesis of this disease remains unclear even though transforming growth factor-β (TGF-β)/smad signalling has been reported to be associated with PD. Recent studies have shown that phosphoinositide 3-kinase (PI3K)/Akt signalling regulates fibrotic responses including collagen synthesis and cell proliferation. Thus, we synthesized HS-173, a novel PI3K inhibitor, and determined whether this compound has anti-fibrotic effects on PD-derived primary fibroblasts. In this study, we found that HS-173 inhibited the growth of fibroblasts in a dose-dependent manner and induced apoptosis. In addition, HS-173 reduced the expression of α-smooth muscle actin (α-SMA), vimentin, PAI-1, fibronectin, collagen type I, collagen IV and TGF-β-activated smad2/3 in PD-derived primary fibroblasts. HS-173 blocked the PI3K/Akt signalling pathway by decreasing the activation of Akt, mTOR and P70S6K. Our results showed that HS-173 suppressed fibrotic responses such as cell proliferation and collagen synthesis by blocking PI3K/Akt signalling in PD-derived primary fibroblasts. Our findings provide molecular insights into the potential therapeutic action of HS-173 through targeting the PI3K/Akt pathway in PD-derived fibroblasts and demonstrated that HS-173 could be used as a pharmacological agent for treating other fibrotic diseases.

show abstract

Section: Discussionmentioning

confidence: 99%

A novel PI3K inhibitor alleviates fibrotic responses in fibroblasts derived from Peyronie’s plaques

Jung

Ryu

Lee

et al. 2013

International Journal of Oncology

View full text Add to dashboard Cite

show abstract

“…One cell line study revealed that cells resistant to tamoxifen can be resensitised to its growth-inhibitory effects by targeting and blocking the action of the NF B pathway [165]. Another group suggested that by inhibiting O-6methylguanine-DNA methyltransferase (MGMT), a DNA repair protein they identified as being overexpressed in some tamoxifen resistant cell lines, sensitivity to tamoxifen could be restored [331]. Another reported that a CDK2 inhibitor could reverse endocrine therapy resistance in tumours overexpressing cyclins-E1 and E2 [104].…”

Section: Combating Resistancementioning

confidence: 99%

Endocrine Resistance in Breast Cancer

Dixon

2014

New Journal of Science

View full text Add to dashboard Cite

Around 70% of all breast cancers are estrogen receptor alpha positive and hence their development is highly dependent on estradiol. While the invention of endocrine therapies has revolusioned the treatment of the disease, resistance to therapy eventually occurs in a large number of patients. This paper seeks to illustrate and discuss the complexity and heterogeneity of the mechanisms which underlie resistance and the approaches proposed to combat them. It will also focus on the use and development of methods for predicting which patients are likely to develop resistance.

show abstract

“…We propose that the augmented turnover of ER in the ER-MGMT complex by fulvestrant also accounts for the enhanced degradation of MGMT we observed in breast cancer cells. The destruction of MGMT in the ER complexes does occur in tamoxifen treated cells, however, to a lower level, as has been implied by previous observations on the ability of BG to overcome tamoxifen resistance [ 28 ] and tamoxifen-induced ubiquitin degradation of MGMT in HT29 cells [ 42 ] . Therefore, our finding on the ability of fulvestrant to trigger MGMT deficiency can be rationally exploited for improved therapy by combining fulvestrant with MGMT-targeted alkylating agents to obtain greater anticancer efficacy.…”

Section: Discussionmentioning

confidence: 69%

“…Previously, a report described the downregulation of MGMT through ubiquitin-proteolysis in tamoxifen treated HT29 cells [ 42 ] . Recently, Bobustuc et al reported a significant upregulation of MGMT in tamoxifen resistant breast cancer cells [ 28 ] . With this background, we sought to determine the estrogenic regulation of MGMT by searching the human MGMT promoter (GenBank: X61657.1) for estrogen response elements and related cis-acting sequences.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2016

View full text Add to dashboard Cite

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.

show abstract

MGMT Inhibition Restores ERα Functional Sensitivity to Antiestrogen Therapy

Cited by 14 publications

References 59 publications

A novel PI3K inhibitor alleviates fibrotic responses in fibroblasts derived from Peyronie’s plaques

A novel PI3K inhibitor alleviates fibrotic responses in fibroblasts derived from Peyronie’s plaques

Endocrine Resistance in Breast Cancer

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

Contact Info

Product

Resources

About