Estrogen receptor β ligation inhibits Hodgkin lymphoma growth by inducing autophagy.

Research output: Contribution to journalArticle

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.
Original languageEnglish
Pages (from-to)8522-8535
Number of pages13
JournalOncotarget
Volume8
Publication statusPublished - 2017

Fingerprint

Autophagy
Hodgkin Disease
Estrogen Receptors
Ligation
Growth
Lymphoma
Neoplasms
SCID Mice
Infertility
Disease-Free Survival
Estradiol
Cell Cycle
Estrogens
Homeostasis
Radiotherapy
Heart Failure
Cell Proliferation
Light
Recurrence
Therapeutics

Keywords

  • estrogen receptor beta
  • Hodgkin's lymphoma

Cite this

@article{f3d67abb79234853818db9056482c91e,
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{\%} ofpatients relapse or fail to make complete remission. In addition, patients whoachieve long-term disease-free survival frequently undergo infertility, secondarymalignancies, and cardiac failure, which are related to chemotherapeutic agentsand radiation therapies. Hence, new therapeutic strategies able to counteract theHL disease in this important patient population are still a matter of study.Estrogens, in particular 17β-estradiol (E2), have been suggested to play a rolein lymphoma cell homeostasis by estrogen receptors (ER) β activation. On thesebases, we investigated whether the ligation of ERβ by a selective agonist, the2,3-bis(4-hydroxyphenyl)-propionitrile (DPN), could impact HL tumor growth. Wefound that DPN-mediated ERβ activation led to a reduction of in vitro cellproliferation and cell cycle progression by inducing autophagy. In nonobesediabetic/severe combined immunodeficient (NOD/SCID) mice engrafted with HL cells,ERβ activation by DPN was able to reduce lymphoma growth up to 60{\%} and thisassociated with the induction of tumor cell autophagy. Molecular characterizationof ERβ-induced autophagy revealed an overexpression of damage-regulated autophagymodulator 2 (DRAM2) molecule, whose role in autophagy modulation is stilldebated. After ERβ activation, both DRAM2 and protein 1 light chain 3 (LC3), akey actor in the autophagosome formation, strictly interacted each other andlocalized at mitochondrial level.Altogether these results suggest that targeting ERβ with selective agonists might affect HL cell proliferation and tumor growthvia a mechanism that brings into play DRAM2-dependent autophagic cascade.",
keywords = "estrogen receptor beta, Hodgkin's lymphoma",
author = "Marina Pierdominici and Angela Maselli and Locatelli, {Silvia L.} and Laura Ciarlo and Giuseppa Careddu and Mario Patrizio and Barbara Ascione and Antonella Tinari and {Carlo Stella}, Carmelo and Walter Malorni and paola matarrese and Elena Ortona",
year = "2017",
language = "English",
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pages = "8522--8535",
journal = "Oncotarget",
issn = "1949-2553",
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TY - JOUR

T1 - Estrogen receptor β ligation inhibits Hodgkin lymphoma growth by inducing autophagy.

AU - Pierdominici, Marina

AU - Maselli, Angela

AU - Locatelli, Silvia L.

AU - Ciarlo, Laura

AU - Careddu, Giuseppa

AU - Patrizio, Mario

AU - Ascione, Barbara

AU - Tinari, Antonella

AU - Carlo Stella, Carmelo

AU - Malorni, Walter

AU - matarrese, paola

AU - Ortona, Elena

PY - 2017

Y1 - 2017

N2 - Although Hodgkin lymphoma (HL) is curable with current therapy, at least 20% ofpatients relapse or fail to make complete remission. In addition, patients whoachieve long-term disease-free survival frequently undergo infertility, secondarymalignancies, and cardiac failure, which are related to chemotherapeutic agentsand radiation therapies. Hence, new therapeutic strategies able to counteract theHL disease in this important patient population are still a matter of study.Estrogens, in particular 17β-estradiol (E2), have been suggested to play a rolein lymphoma cell homeostasis by estrogen receptors (ER) β activation. On thesebases, we investigated whether the ligation of ERβ by a selective agonist, the2,3-bis(4-hydroxyphenyl)-propionitrile (DPN), could impact HL tumor growth. Wefound that DPN-mediated ERβ activation led to a reduction of in vitro cellproliferation and cell cycle progression by inducing autophagy. In nonobesediabetic/severe combined immunodeficient (NOD/SCID) mice engrafted with HL cells,ERβ activation by DPN was able to reduce lymphoma growth up to 60% and thisassociated with the induction of tumor cell autophagy. Molecular characterizationof ERβ-induced autophagy revealed an overexpression of damage-regulated autophagymodulator 2 (DRAM2) molecule, whose role in autophagy modulation is stilldebated. After ERβ activation, both DRAM2 and protein 1 light chain 3 (LC3), akey actor in the autophagosome formation, strictly interacted each other andlocalized at mitochondrial level.Altogether these results suggest that targeting ERβ with selective agonists might affect HL cell proliferation and tumor growthvia a mechanism that brings into play DRAM2-dependent autophagic cascade.

AB - Although Hodgkin lymphoma (HL) is curable with current therapy, at least 20% ofpatients relapse or fail to make complete remission. In addition, patients whoachieve long-term disease-free survival frequently undergo infertility, secondarymalignancies, and cardiac failure, which are related to chemotherapeutic agentsand radiation therapies. Hence, new therapeutic strategies able to counteract theHL disease in this important patient population are still a matter of study.Estrogens, in particular 17β-estradiol (E2), have been suggested to play a rolein lymphoma cell homeostasis by estrogen receptors (ER) β activation. On thesebases, we investigated whether the ligation of ERβ by a selective agonist, the2,3-bis(4-hydroxyphenyl)-propionitrile (DPN), could impact HL tumor growth. Wefound that DPN-mediated ERβ activation led to a reduction of in vitro cellproliferation and cell cycle progression by inducing autophagy. In nonobesediabetic/severe combined immunodeficient (NOD/SCID) mice engrafted with HL cells,ERβ activation by DPN was able to reduce lymphoma growth up to 60% and thisassociated with the induction of tumor cell autophagy. Molecular characterizationof ERβ-induced autophagy revealed an overexpression of damage-regulated autophagymodulator 2 (DRAM2) molecule, whose role in autophagy modulation is stilldebated. After ERβ activation, both DRAM2 and protein 1 light chain 3 (LC3), akey actor in the autophagosome formation, strictly interacted each other andlocalized at mitochondrial level.Altogether these results suggest that targeting ERβ with selective agonists might affect HL cell proliferation and tumor growthvia a mechanism that brings into play DRAM2-dependent autophagic cascade.

KW - estrogen receptor beta

KW - Hodgkin's lymphoma

M3 - Article

VL - 8

SP - 8522

EP - 8535

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

ER -