Estrogens and alkylphenols promote proliferation of the seminoma-like TCam-2 cell line trough ERΑ36-dependent pathways - Archive ouverte HAL Accéder directement au contenu
Communication Dans Un Congrès Année : 2012

Estrogens and alkylphenols promote proliferation of the seminoma-like TCam-2 cell line trough ERΑ36-dependent pathways

Résumé

Background: Seminoma, originated from carcinoma in situ cells (CIS), is one of the main causes of cancer in young men. Postpubertal developmentof these testicular germ cell tumors suggests a hormone-sensitive way of CIS cell proliferation induction probably stimulated by lifelong exposure to endocrine disruptors. In a first step to understand the mechanisms underlying the deleterious effects of endocrine disrupting compounds on germ cells, we aimed to decipher the estrogen-dependent transduction pathways in TCam2 cells. Then, we began to assess the effects of a [4tert-octyl + 4-nonylphenol] mix on testicular germ cell tumors in vitro and in vivo. Material and Methods: In this study, we used the unique seminoma TCam-2 cell line which do not express the canonical ERa66 estrogen receptor but Era36, a truncated isoform retaining the DNA-binding, partial dimerisation and ligand-binding domains and a specific C-term 27 aa sequence. Cells were exposed to either estradiol at concentrations in the range of those detected in an adult human testis or to a [4tert-octyl + 4-nonylphenol] mix used at low doses − i.e. those found in food and drinking water. In vitro, we performed cell proliferation assays, siRNA- or shRNA-directed knockdown, microarray- directed gene targeting and signaling pathways identification after short term (1h) or mid-term (24h or 48h) treatment. We also addressed the question of TCam-2 derived tumor growth in xenografted Nude mice treated with the [4tert-octyl + 4-nonylphenol] mix. Results: We demonstrate in vitro that estradiol and the alkylphenol mix trigger TCam-2 cell proliferation through ERa36-dependent pathways. We establish that estradiol can activate GPER-cAMP/PKA signaling pathway. Stable ERa36 knockdown indicates that ERa36 is (i) necessary for cell proliferation (ii) a downstream target of estradiol-activated GPER/PKA/CREB pathway, (iii) required for estradiol-dependent EGFR expression. The [4tert-octyl + 4-nonylphenol] mix signaling pathway is clearly ERa36 dependent but seems to be partially non-estrogenic. Finally, we show that the [4tert-octyl+ 4-nonylphenol] mix stimulates tumor growth in TCam-2 xenografted Nude mice. Conclusions: Our results highlight the functional role of ERa36 in context of seminoma cell proliferation and the importance of testing ERa36 in vivo as apossible marker for endocrine disruptor susceptibility

Domaines

Cancer

Dates et versions

hal-00747345 , version 1 (31-10-2012)

Identifiants

Citer

Hussein Ajj, Angelina Wallacides, Stéphane Flament, Amand Chesnel, Hélène Dumond. Estrogens and alkylphenols promote proliferation of the seminoma-like TCam-2 cell line trough ERΑ36-dependent pathways. 22nd Biennial Congress of the European Association for Cancer Research, EACR-22, Jul 2012, Barcelone, Spain. pp.CDROM, ⟨10.1016/S0959-8049(12)70981-4⟩. ⟨hal-00747345⟩

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