title: Dual PI3K/ERK inhibition induces necroptotic cell death of Hodgkin Lymphoma cells through IER3 downregulation.
abstract: PI3K/AKT and RAF/MEK/ERK pathways are constitutively activated in Hodgkin lymphoma (HL) patients, thus representing attractive therapeutic targets. Here we report that the PI3K/ERK dual inhibitor AEZS-136 induced significant cell proliferation inhibition in L-540, SUP-HD1, KM-H2 and L-428 HL cell lines, but a significant increase in necroptotic cell death was observed only in two out of four cell lines (L-540 and SUP-HD1). In these cells, AEZS-136-induced necroptosis was associated with mitochondrial dysfunction and reactive oxygen species (ROS) production. JNK was activated by AEZS-136, and AEZS-136-induced necroptosis was blocked by the necroptosis inhibitor necrostatin-1 or the JNK inhibitor SP600125, suggesting that JNK activation is required to trigger necroptosis following dual PI3K/ERK inhibition. Gene expression analysis indicated that the effects of AEZS-136 were associated with the modulation of cell cycle and cell death pathways. In the cell death-resistant cell lines, AEZS-136 induced the expression of immediate early response 3 (IER3) both in vitro and in vivo. Silencing of IER3 restored sensitivity to AEZS-136-induced necroptosis. Furthermore, xenograft studies demonstrated a 70% inhibition of tumor growth and a 10-fold increase in tumor necrosis in AEZS-136-treated animals. Together, these data suggest that dual PI3K/ERK inhibition might be an effective approach for improving therapeutic outcomes in HL.
authors: Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Italy.
authors: Silvia Laura
authors: SL
authors: Locatelli
authors: Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Italy.
authors: Giuseppa
authors: G
authors: Careddu
authors: Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Italy.
authors: Giuliano Giuseppe
authors: GG
authors: Stirparo
authors: Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Italy.
authors: Luca
authors: L
authors: Castagna
authors: Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Italy.|Humanitas University, Rozzano, Italy.
authors: Armando
authors: A
authors: Santoro
authors: Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Italy.|Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
authors: Carmelo
authors: C
authors: Carlo-Stella
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006689:Hodgkin Disease / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D009336:Necrosis; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011719:Pyrazines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D051017:Apoptosis Regulatory Proteins; D004791:Enzyme Inhibitors; C099815:IER3 protein, human; D008565:Membrane Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011719:Pyrazines; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D020929:Mitogen-Activated Protein Kinase Kinases