Modulation of 17β-Estradiol Signaling on Cellular Proliferation by Caveolin-2.

Published on Jun 1, 2016in Journal of Cellular Physiology5.546
· DOI :10.1002/JCP.25218
Pierangela Totta16
Estimated H-index: 16
,
Fabio Gionfra1
Estimated H-index: 1
+ 1 AuthorsFilippo Acconcia30
Estimated H-index: 30
Sources
Abstract
The sex hormone 17β-estradiol (E2) exerts pleiotropic effects by binding to the ligand-activated transcription factor estrogen receptor α (ERα). The E2:ERα complex regulates several physiological processes, including cell survival and proliferation, through transcriptional effects (i.e., estrogen responsive element [ERE]-based gene transcription) and non-transcriptional membrane-initiated effects (i.e., the activation of extra-nuclear signaling cascades), which derive from the activation of the pool of ERα that is localized to plasma membrane caveolae. Caveolae are ω-shaped membrane sub-domains that are composed of scaffold proteins named caveolins (i.e., caveolin-1, caveolin-2, and caveolin-3). Although caveolin-3 is exclusively expressed in muscles, caveolin-1 and caveolin-2 are co-expressed in all human tissues. From a functional point of view, caveolin-2 can operate both dependently on and independently of caveolin-1, which is the main coat component of caveolae. Interestingly, while a functional interplay between caveolin-1 and ERα has been reported in the control of E2-induced physiological effects, the role of caveolin-2 in E2:ERα signaling within the cell remains poorly understood. This study shows that siRNA-mediated caveolin-2 depletion in breast ductal carcinoma cells (MCF-7) reduces E2-induced ERα phosphorylation at serine residue 118 (S118), controls intracellular receptor levels, precludes ERα-mediated extra-nuclear activation of signaling pathways, reduces ERα transcriptional activity, and prevents cellular proliferation. Meanwhile, the impact of caveolin-1 depletion on ERα signaling in MCF-7 cells is shown to be similar to that elicited by siRNA-mediated caveolin-2 depletion. Altogether, these data demonstrate that caveolin-2 expression is necessary for the control of E2-dependent cellular proliferation. J. Cell. Physiol. 9999: 1–7, 2015. © 2015 Wiley Periodicals, Inc.
📖 Papers frequently viewed together
83 Citations
20055.98Glia
50 Citations
41 Citations
References33
Newest
#1Pierangela TottaH-Index: 16
#2Valeria PesiriH-Index: 7
Last. Filippo AcconciaH-Index: 30
view all 5 authors...
17β-estradiol (E2)-induced signaling and control of estrogen receptor (ER)α degradation both play a major role in breast cancer cell proliferation. We recently reported the involvement of lysosomal function in both E2-dependent ERα breakdown and E2-induced cell proliferation and thus hypothesized a role for endocytic proteins in ERα signaling. An small interfering RNA screen identified proteins that regulate intracellular endocytic traffic and whose silencing alters E2-induced ERα degradation. O...
15 CitationsSource
#1Valeria PesiriH-Index: 7
#2Pierangela TottaH-Index: 16
Last. Filippo AcconciaH-Index: 30
view all 4 authors...
The sex steroid hormone 17β-estradiol (E2) regulates breast cancer (BC) cell proliferation and migration through the activation of a plethora of signal transduction cascades (e.g., PI3K/AKT activation) starting after E2 binding to the estrogen receptor alpha (ERα). The activity of the ubiquitin (Ub)-system modulates many physiological processes (e.g., cell proliferation and migration), and recently, a specific inhibitor (Pyr-41) of the Ub-activating enzyme (E1), which works as the activator of t...
9 CitationsSource
#1Ali Pedram (UCI: University of California, Irvine)H-Index: 45
#2Mahnaz RazandiH-Index: 36
Last. Ellis R. Levin (UCI: University of California, Irvine)H-Index: 59
view all 5 authors...
Summary Steroid receptors are found in discrete cellular locations, but it is unknown whether extranuclear pools are necessary for normal organ development. To assess this, we developed a point mutant estrogen receptor α (ERα) knockin mouse (C451A) that precludes palmitoylation and membrane trafficking of the steroid receptor in all organs. Homozygous knockin female mice (nuclear-only ERα [NOER]) show loss of rapid signaling that occurs from membrane ERα in wild-type mice. Multiple developmental...
108 CitationsSource
#1Rui Wang (HUST: Huazhong University of Science and Technology)H-Index: 8
#2Zhi Li (HUST: Huazhong University of Science and Technology)H-Index: 7
Last. Tao Huang (HUST: Huazhong University of Science and Technology)H-Index: 37
view all 7 authors...
: Previous studies have demonstrated that caveolin 1 acts as a tumor suppressor in breast cancer, however, few studies have demonstrated that caveolin 1 also serves as a tumor promoter in breast cancer. In the present study, caveolin 1 small interfering RNA was used to knock down caveolin 1 expression in order to investigate the association between caveolin 1 and the proliferation and metastatic abilities of human breast cancer BT474 cells. The results revealed that cell proliferation, migration...
14 CitationsSource
#1Pierangela TottaH-Index: 16
#2Valeria PesiriH-Index: 7
Last. Filippo AcconciaH-Index: 30
view all 4 authors...
The homeostatic control of the cellular proteome steady-state is dependent either on the 26S proteasome activity or on the lysosome function. The sex hormone 17β-estradiol (E2) controls a plethora of biological functions by binding to the estrogen receptor α (ERα), which is both a nuclear ligand-activated transcription factor and also an extrinsic plasma membrane receptor. Regulation of E2-induced physiological functions (e.g., cell proliferation) requires the synergistic activation of both tran...
27 CitationsSource
#1Marine Adlanmerini (University of Toulouse)H-Index: 7
#2Romain Solinhac (University of Toulouse)H-Index: 9
Last. Françoise Lenfant (University of Toulouse)H-Index: 35
view all 20 authors...
Estrogen receptor alpha (ERα) activation functions AF-1 and AF-2 classically mediate gene transcription in response to estradiol (E2). A fraction of ERα is targeted to plasma membrane and elicits membrane-initiated steroid signaling (MISS), but the physiological roles of MISS in vivo are poorly understood. We therefore generated a mouse with a point mutation of the palmitoylation site of ERα (C451A-ERα) to obtain membrane-specific loss of function of ERα. The abrogation of membrane localization ...
155 CitationsSource
#1Hery Urra (University of Chile)H-Index: 14
#2Vicente A. Torres (University of Chile)H-Index: 23
Last. Andrew F. G. Quest (University of Chile)H-Index: 45
view all 9 authors...
Caveolin-1 is known to promote cell migration, and increased caveolin-1 expression is associated with tumor progression and metastasis. In fibroblasts, caveolin-1 polarization and phosphorylation of tyrosine-14 are essential to promote migration. However, the role of caveolin-1 in migration of metastatic cells remains poorly defined. Here, caveolin-1 participation in metastatic cell migration was evaluated by shRNA targeting of endogenous caveolin-1 in MDA-MB-231 human breast cancer cells and ec...
55 CitationsSource
#1Piergiorgio La RosaH-Index: 13
#1Piergiorgio La Rosa (Roma Tre University)H-Index: 2
Last. Filippo AcconciaH-Index: 30
view all 5 authors...
The estrogen receptor-α (ERα) is a transcription factor that regulates gene expression through the binding to its cognate hormone 17β-estradiol (E2). ERα transcriptional activity is regulated by E2-evoked 26S proteasome-mediated ERα degradation and ERα serine (S) residue 118 phosphorylation. Furthermore, ERα mediates fast cell responses to E2 through the activation of signaling cascades such as the MAPK/ERK and phosphoinositide-3-kinase/v-akt murine thymoma viral oncogene homolog 1 pathways. The...
83 CitationsSource
#1Ali Pedram (UCI: University of California, Irvine)H-Index: 45
#2Mahnaz RazandiH-Index: 36
Last. Ellis R. Levin (UCI: University of California, Irvine)H-Index: 59
view all 4 authors...
Classical estrogen, progesterone, and androgen receptors (ERs, PRs, and ARs) localize outside the nucleus at the plasma membrane of target cells. From the membrane, the receptors signal to activate kinase cascades that are essential for the modulation of transcription and nongenomic functions in many target cells. ER, PR, and AR trafficking to the membrane requires receptor palmitoylation by palmitoylacyltransferase (PAT) protein(s). However, the identity of the steroid receptor PAT(s) is unknow...
99 CitationsSource
#1Filippo AcconciaH-Index: 30
#2Maria Adele MarinoH-Index: 18
Last. Maria MarinoH-Index: 43
view all 2 authors...
Two different isoforms of the estrogen receptors (i.e., ERα and ERβ) mediate pleiotropic 17β-estradiol (E2)-induced cellular effects. The ERs are principally localized in the nucleus where they act by globally modifying the expression of the E2-target genes. The premise that E2 effects are exclusively mediated through the nuclear localized ERs has been rendered obsolete by research over the last 15 years demonstrating that ERα and ERβ proteins are also localized at the plasma membranes and in ot...
64 CitationsSource
Cited By17
Newest
17β-Estradiol (E2) controls diverse physiological processes, including cell proliferation, through its binding to estrogen receptor α (ERα). E2:ERα signaling depends on both the receptor subcellular localization (e.g., nucleus, plasma membrane) and intracellular ERα abundance. Indeed, the control of ERα levels is necessary for the effects of E2, and E2 itself induces ERα degradation and cell proliferation in parallel. Thus, the modulation of intracellular ERα levels is a critical parameter for E...
3 CitationsSource
Source
#1Xian-Ling Qian (NCU: Nanchang University)H-Index: 5
#2Yi-Hang Pan (NCU: Nanchang University)H-Index: 1
Last. Li-Xia Xiong (NCU: Nanchang University)H-Index: 10
view all 7 authors...
: Human breast cancer is one of the most frequent cancer diseases and causes of death among female population worldwide. It appears at a high incidence and has a high malignancy, mortality, recurrence rate and poor prognosis. Caveolin-1 (Cav1) is the main component of caveolae and participates in various biological events. More and more experimental studies have shown that Cav1 plays a critical role in the progression of breast cancer including cell proliferation, apoptosis, autophagy, invasion,...
17 CitationsSource
#1Liliana del Valle Sosa (National University of Cordoba)H-Index: 9
#2Juan Pablo Petiti (National University of Cordoba)H-Index: 11
Last. Alicia Inés Torres (National University of Cordoba)H-Index: 16
view all 10 authors...
: The molecular mechanisms underlying the ERα nuclear/cytoplasmic pool that modulates pituitary cell proliferation have been widely described, but it is still not clear how ERα is targeted to the plasma membrane. The aim of this study was to analyse ERα palmitoylation and the plasma membrane ERα (mERα) pool, and their participation in E2-triggered membrane-initiated signalling in normal and pituitary tumour cell growth. Cell cultures were prepared from anterior pituitaries of female Wistar rats ...
5 CitationsSource
Abstract With the advent of omic technologies, our understanding of the molecular mechanisms underlying estrogen receptor α (ERα)-expressing breast cancer (BC) progression has grown exponentially. Nevertheless, the most widely used therapy for inhibiting this disease is endocrine therapy (ET) (i.e., aromatase inhibitors, tamoxifen - Tam, faslodex/fulvestrant - FUL). However, in a considerable number of cases, prolonged patient treatment with ET generates the development of resistant tumor cells ...
16 CitationsSource
#1Claudia BusoneroH-Index: 8
#2Stefano LeoneH-Index: 21
Last. Filippo AcconciaH-Index: 30
view all 4 authors...
Purpose Most breast cancers (BCs) express estrogen receptor α (ERα) and are treated with the endocrine therapy (ET) drugs 4OH-tamoxifen (Tam) and fulvestrant (ICI 182,780; ICI). Unfortunately, a high fraction of ET treated women relapses and becomes resistant to ET. Therefore, additional anti-BC drugs are needed. Recently, we proposed that the identification of novel anti-BC drugs can be achieved using modulation of the intracellular ERα content in BC cells as a pharmacological target. Here, we ...
7 CitationsSource
#1Claudia BusoneroH-Index: 8
#2Stefano LeoneH-Index: 21
Last. Filippo AcconciaH-Index: 30
view all 4 authors...
Purpose: Most breast cancers (BCs) express estrogen receptor α (ERα) and are treated with the endocrine therapy (ET) drugs 4OH-tamoxifen (Tam) and fulvestrant (i.e., ICI182,780-ICI). Unfortunately, a high fraction of ET-treated women relapses and become resistant to ET. Therefore, additional anti-BC drugs are needed. Recently, we proposed that the identification of novel anti-BC drugs can be achieved using the modulation of the ERα intracellular content in BC cells as a pharmacological target. H...
1 CitationsSource
#1Ping OuyangH-Index: 3
#2Bode LinH-Index: 3
Last. Zhigang HuangH-Index: 3
view all 7 authors...
Abstract Our preview studies showed TPI gene which encodes the Triosephosphate isomerase was overexpressed in human gastric cancer (GC) tissues. However, the potential molecular mechanisms how TPI influences the GC development is not clear. Here, we performed global gene expression profiling for TPI knockdown using microarrays in human GC cell line MGC-803 cells. The differentially expressed genes (DEGs) were identified using reverse transcription-quantitative polymerase chain reaction analysis....
3 CitationsSource
Abstract Most cases of breast cancer (BC) are estrogen receptor α-positive (ERα+) at diagnosis. The presence of ERα drives the therapeutic approach for this disease, which often consists of endocrine therapy (ET). 4OH-Tamoxifen and faslodex (i.e., fulvestrant - ICI182,780) are two ETs that render tumor cells insensitive to 17β-estradiol (E2)-dependent proliferative stimuli and prevent BC progression. However, ET has limitations and serious failures in different tissues and organs. Thus, there is...
9 CitationsSource
Abstract The hormone 17β-estradiol (E2) contributes to body homeostasis maintenance by regulating many different physiological functions in both male and female organs. E2 actions in reproductive and non-reproductive tissues rely on a complex net of nuclear and extra-nuclear signal transduction pathways triggered by at least two estrogen receptor subtypes (ERα and ERβ). Consequently, the de-regulation of E2:ER signaling contributes to the pathogenesis of many diseases including cancer. Among oth...
29 CitationsSource