title: Estrogen receptor β ligation inhibits Hodgkin lymphoma growth by inducing autophagy.
abstract: Although Hodgkin lymphoma (HL) is curable with current therapy, at least 20% of patients relapse or fail to make complete remission. In addition, patients who achieve long-term disease-free survival frequently undergo infertility, secondary malignancies, and cardiac failure, which are related to chemotherapeutic agents and radiation therapies. Hence, new therapeutic strategies able to counteract the HL disease in this important patient population are still a matter of study. Estrogens, in particular 17β-estradiol (E2), have been suggested to play a role in lymphoma cell homeostasis by estrogen receptors (ER) β activation. On these bases, we investigated whether the ligation of ERβ by a selective agonist, the 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN), could impact HL tumor growth. We found that DPN-mediated ERβ activation led to a reduction of in vitro cell proliferation and cell cycle progression by inducing autophagy. In nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice engrafted with HL cells, ERβ activation by DPN was able to reduce lymphoma growth up to 60% and this associated with the induction of tumor cell autophagy. Molecular characterization of ERβ-induced autophagy revealed an overexpression of damage-regulated autophagy modulator 2 (DRAM2) molecule, whose role in autophagy modulation is still debated. After ERβ activation, both DRAM2 and protein 1 light chain 3 (LC3), a key actor in the autophagosome formation, strictly interacted each other and localized at mitochondrial level.Altogether these results suggest that targeting ERβ with selective agonists might affect HL cell proliferation and tumor growth via a mechanism that brings into play DRAM2-dependent autophagic cascade.
authors.affiliation: Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Pierdominici
authors.affiliation: Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Maselli
authors.affiliation: Department of Oncology and Hematology, Humanitas Cancer Center - Humanitas Clinical and Research Center, Milano, Italy.
authors.forename: Silvia L
authors.initials: SL
authors.lastname: Locatelli
authors.affiliation: Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Ciarlo
authors.affiliation: Department of Oncology and Hematology, Humanitas Cancer Center - Humanitas Clinical and Research Center, Milano, Italy.
authors.forename: Giuseppa
authors.initials: G
authors.lastname: Careddu
authors.affiliation: Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Patrizio
authors.affiliation: Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Ascione
authors.affiliation: Department of Technology and Health, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Tinari
authors.affiliation: Department of Oncology and Hematology, Humanitas Cancer Center - Humanitas Clinical and Research Center, Milano, Italy.
authors.forename: Carmelo
authors.initials: C
authors.lastname: Carlo-Stella
authors.affiliation: Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Walter
authors.initials: W
authors.lastname: Malorni
authors.affiliation: Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Matarrese
authors.affiliation: Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Ortona
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006689:Hodgkin Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008024:Ligands; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D011422:Propionates
chemical_list: D047629:Estrogen Receptor beta; D008024:Ligands; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009570:Nitriles; D020845:Selective Estrogen Receptor Modulators; C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D011422:Propionates; C544299:DRAM2 protein, human; C000600034:ESR2 protein, human; C477012:MAP1LC3A protein, human
keywords: DRAM2; Hodgkin lymphoma; autophagy; estrogen receptor β; tumor growth