The extra-nuclear interactome of the estrogen receptors: implications for physiological functions

Acconcia, Filippo; Fiocchetti, Marco; Busonero, Claudia; Fernandez, Virginia Solar; Montalesi, Emiliano; Cipolletti, Manuela; Pallottini, Valentina; Marino, Maria

doi:10.1016/j.mce.2021.111452

Cited by 24 publications

(43 citation statements)

References 189 publications

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“…Next, we evaluated the ERα's ability to activate a synthetic ERE-containing reporter gene stably transfected in MCF-7 cells [ 12 ] in the presence and the absence of both the above-indicated kinase inhibitors and E2. As expected [ 38 ], E2 increased the ERα transcriptional activity (Fig. 9 B).…”

Section: Resultssupporting

confidence: 89%

“…Ligand-induced ERα reduction in BC cells can be due to the ability of the ligand to directly bind to the receptor [ 38 ]. In turn, ERα binding assays were performed with different doses of AZD, MK, VE, Prexa, GDC, and E2, to test whether these kinase inhibitors could directly bind ERα in vitro .…”

Section: Resultsmentioning

confidence: 99%

“…The ERα is a ligand-activated transcription factor, which becomes activated upon E2 binding by phosphorylation at S118 and drives the transcription of those genes containing the estrogen response element (ERE) within their promoter regions [ 38 ]. In turn, we treated MCF-7 cells with E2 after the administration of AZD, VE, KU, MK, and CCT and detected ERα phosphorylation at S118.…”

Section: Resultsmentioning

confidence: 99%

“…The E2-dependent activation of ERα in BC cells results in DNA synthesis, cell cycle progression, and cell proliferation [ 34 , 38 ]. In turn, we studied the effect of AZD on the E2 ability to induce cell proliferation in MCF-7 cells.…”

Section: Resultsmentioning

confidence: 99%

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Clinically relevant CHK1 inhibitors abrogate wild-type and Y537S mutant ERα expression and proliferation in luminal primary and metastatic breast cancer cells

Pescatori

Leone

Cipolletti

et al. 2022

J Exp Clin Cancer Res

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Background Challenges exist in the clinical treatment of luminal estrogen receptor α (ERα)-positive breast cancers (BCs) both to prevent resistance to endocrine therapy (ET) and to treat ET-resistant metastatic BCs (MBC). Therefore, we evaluated if kinases could be new targets for the treatment of luminal primary and MBCs. Methods ~ 170 kinase inhibitors were applied to MCF-7 cells either with adaptative or genetic resistance to ET drugs and both ERα levels and cell proliferation were measured. Robust-Z-score calculation identified AZD7762 (CHK1/CHK2 inhibitor) as a positive hit. Subsequently, Kaplan–Meier analyses of CHK1 and CHK2 impact on ERα-positive BC patients relapse-free-survival (RFS), bioinformatic evaluations of CHK1 and CHK2 expression and activation status as a function of ERα activation status as well as drug sensitivity studies in ERα-positive BC cell lines, validation of the impact of the ATR:CHK1 and ATM:CHK2 pathways on the control of ERα stability and BC cell proliferation via inhibitor- and siRNA-based approaches, identification of the molecular mechanism required for inhibitor-dependent ERα degradation in BC and the impact of CHK1 and CHK2 inhibition on the 17β-estradiol (E2):ERα signaling, synergy proliferation studies between ET-drugs and clinically relevant CHK1 inhibitors in different luminal BC cell lines, were performed. Results A reduced CHK1 expression correlates with a longer RFS in women with ERα-positive BCs. Interestingly, women carrying luminal A BC display an extended RFS when expressing low CHK1 levels. Accordingly, CHK1 and ERα activations are correlated in ERα-positive BC cell lines, and the ATR:CHK1 pathway controls ERα stability and cell proliferation in luminal A BC cells. Mechanistically, the generation of DNA replication stress rather than DNA damage induced by ATR:CHK1 pathway inhibition is a prerequisite for ERα degradation. Furthermore, CHK1 inhibition interferes with E2:ERα signaling to cell proliferation, and drugs approved for clinical treatment of primary and MBC (4OH-tamoxifen and the CDK4/CDK6 inhibitors abemaciclib and palbociclib) exert synergic effects with the CHK1 inhibitors in clinical trials for the treatment of solid tumors (AZD7762, MK8776, prexasertib) in preventing the proliferation of cells modeling primary and MBC. Conclusions CHK1 could be considered as an appealing novel pharmacological target for the treatment of luminal primary and MBCs.

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Section: Resultssupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Clinically relevant CHK1 inhibitors abrogate wild-type and Y537S mutant ERα expression and proliferation in luminal primary and metastatic breast cancer cells

Pescatori

Leone

Cipolletti

et al. 2022

J Exp Clin Cancer Res

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“…Much less is known about the involvement of non-GPER membrane ERs in neuroprotection against hypoxic/ischemic injury. GPER1 mainly involves PKA, PKB, and ERK signaling cascades and phosphoinositide-3-kinase (PI3K), in addition to G-proteins (Gα s , Gα i ); in contrast, non-GPER membrane ERs act preferably via Ca 2+ liberation from intracellular stores, PLC, PKC, Src/ERK, PI3K/AKT, p38/ MAPK, JAK/STAT, Pak1, and FAK (Acconcia et al 2021).…”

Section: Discussionmentioning

confidence: 99%

Posttreatment Strategy Against Hypoxia and Ischemia Based on Selective Targeting of Nonnuclear Estrogen Receptors with PaPE-1

et al. 2021

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Newly synthesized Pathway Preferential Estrogen-1 (PaPE-1) selectively activates membrane estrogen receptors (mERs), namely, mERα and mERβ, and has been shown to evoke neuroprotection; however, its effectiveness in protecting brain tissue against hypoxia and ischemia has not been verified in a posttreatment paradigm. This is the first study showing that a 6-h delayed posttreatment with PaPE-1 inhibited hypoxia/ischemia-induced neuronal death, as indicated by neutral red uptake in mouse primary cell cultures in vitro. The effect was accompanied by substantial decreases in neurotoxicity and neurodegeneration in terms of LDH release and Fluoro-Jade C staining of damaged cells, respectively. The mechanisms of the neuroprotective action of PaPE-1 also involved apoptosis inhibition demonstrated by normalization of both mitochondrial membrane potential and expression levels of apoptosis-related genes and proteins such as Fas, Fasl, Bcl2, FAS, FASL, BCL2, BAX, and GSK3β. Furthermore, PaPE-1-evoked neuroprotection was mediated through a reduction in ROS formation and restoration of cellular metabolic activity that had become dysregulated due to hypoxia and ischemia. These data provide evidence that targeting membrane non-GPER estrogen receptors with PaPE-1 is an effective therapy that protects brain neurons from hypoxic/ischemic damage, even when applied with a 6-h delay from injury onset.

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Exploring Raloxifene‐Based Metallodrugs: A Versatile Vector Combined with Platinum(II), Palladium(II) and Nickel(II) Dichlorides and Carborates against Triple‐Negative Breast Cancer

Kazimir,

Götze,

Lönnecke

et al. 2024

ChemMedChem

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Triple‐negative breast cancer (TNBC) poses challenges in therapy due to the absence of target expression such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Frequently, the treatment of TNBC involves the combination of several therapeutics. However, an enhanced therapeutic effect can be also achieved within a single molecule. The efficacy of raloxifene can be improved by designing a raloxifene‐based hybrid drug bearing a 2,2’‐bipyridine moiety (2). Integration of platinum(II), palladium(II), and nickel(II) complexes into this structure dramatically changed the cytotoxicity. The platinum(II) dichloride complex 3 did not demonstrate any activity, while palladium(II) and nickel(II) dichloride complexes 4 and 5 exhibited various cytotoxic behavior towards different types of hormone‐receptor positive (HR+) cancer and TNBC cell lines. The replacement of the two chlorido ligands in 3‒5 with a dicarbollide (carborate) ion [C2B9H11]2‐ resulted in reduced activity of compounds 6, 7, and 8. However, the palladacarborane complex 7 demonstrated higher selectivity towards TNBC. Furthermore, the mechanism of action was shifted from cytotoxic to explicitly cytostatic with detectable proliferation arrest and accelerated aging, characterized by senescence‐associated phenotype of TNBC cells. This study provides valuable insights into the development of hybrid therapeutics against TNBC.

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The extra-nuclear interactome of the estrogen receptors: implications for physiological functions

Cited by 24 publications

References 189 publications

Clinically relevant CHK1 inhibitors abrogate wild-type and Y537S mutant ERα expression and proliferation in luminal primary and metastatic breast cancer cells

Clinically relevant CHK1 inhibitors abrogate wild-type and Y537S mutant ERα expression and proliferation in luminal primary and metastatic breast cancer cells

Posttreatment Strategy Against Hypoxia and Ischemia Based on Selective Targeting of Nonnuclear Estrogen Receptors with PaPE-1

Exploring Raloxifene‐Based Metallodrugs: A Versatile Vector Combined with Platinum(II), Palladium(II) and Nickel(II) Dichlorides and Carborates against Triple‐Negative Breast Cancer

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