Estrogen receptor β ligation inhibits Hodgkin lymphoma growth by inducing autophagy

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 17 beta-estradiol (E2), have been suggested to play a role in lymphoma cell homeostasis by estrogen receptors (ER) beta activation. On these bases, we investigated whether the ligation of ER beta by a selective agonist, the 2,3-bis(4-hydroxyphenyl)propionitrile (DPN), could impact HL tumor growth. We found that DPN-mediated ER beta 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, ER beta 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 ER beta-induced autophagy revealed an overexpression of damage-regulated autophagy modulator 2 (DRAM2) molecule, whose role in autophagy modulation is still debated. After ER beta 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 ER beta with selective agonists might affect HL cell proliferation and tumor growth via a mechanism that brings into play DRAM2-dependent autophagic cascade.