title: Growth inhibitory effect of rapamycin in Hodgkin-lymphoma cell lines characterized by constitutive NOTCH1 activation.
abstract: Growing evidence suggests that deregulation of signalling elements of Notch and mammalian target of rapamycin (mTOR) pathways contribute to tumorigenesis. These signals play important roles in cellular functions and malignancies. Their tumorigenic role in T-cell acute lymphoblastic leukaemia (T-ALL) is well known; however, their potential interactions and functions are poorly characterized in Hodgkin lymphoma (HL). The aim of our study was to characterize mTOR and Notch signalling elements in HL cell lines (DEV, L1236, KMH2) and human biopsies and to investigate their cross-talk in the tumorous process. High mTOR activity and constitutive NOTCH1 activation was confirmed in HL cell lines, without any known oncogenic mutations in key elements, including those common to both pathways. The anti-tumour effect of Notch inhibitors are well known from several preclinical models but resistance and side effects occur in many cases. Here, we tested mTOR and Notch inhibitors and their combinations in gamma-secretase inhibitor (GSI) resistant HL cells in vitro and in vivo. mTOR inhibitor alone or in combination was able to reduce tumour growth; furthermore, it was more effective in xenograft models in vivo. Based on these results, we suggest that constitutively activated NOTCH1 may be a potential target in HL therapy; furthermore, mTOR inhibitors may be effective for decreasing tumour growth if resistance to Notch inhibitors develop.
authors.affiliation: 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, 26 Üllői út, Budapest, 1085, Hungary.
authors.forename: Noémi
authors.initials: N
authors.lastname: Nagy
authors.affiliation: 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, 26 Üllői út, Budapest, 1085, Hungary.
authors.forename: Melinda
authors.initials: M
authors.lastname: Hajdu
authors.affiliation: 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, 26 Üllői út, Budapest, 1085, Hungary.
authors.forename: Ágnes
authors.initials: Á
authors.lastname: Márk
authors.affiliation: 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, 26 Üllői út, Budapest, 1085, Hungary.|Lendület Molecular Oncohematology Research Group of Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary.
authors.forename: Péter Attila
authors.initials: PA
authors.lastname: Király
authors.affiliation: 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, 26 Üllői út, Budapest, 1085, Hungary.
authors.forename: Mónika
authors.initials: M
authors.lastname: Tóth
authors.affiliation: 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, 26 Üllői út, Budapest, 1085, Hungary.
authors.forename: Titanilla
authors.initials: T
authors.lastname: Dankó
authors.affiliation: 2nd Department of Pediatrics, Semmelweis University, 7-9 Tűzoltó u, Budapest, 1094, Hungary.
authors.forename: Mónika
authors.initials: M
authors.lastname: Csóka
authors.affiliation: 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, 26 Üllői út, Budapest, 1085, Hungary. anna@korb1.sote.hu.|Tumour Progression Research Group of Joint Research Organization of Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary. anna@korb1.sote.hu.
authors.forename: Anna
authors.initials: A
authors.lastname: Sebestyén
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006689:Hodgkin Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007124:Immunoenzyme Techniques; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D014408:Biomarkers, Tumor; C497761:NOTCH1 protein, human; D012333:RNA, Messenger; D051881:Receptor, Notch1; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Gamma secretase inhibitor (GSI) resistance; Hodgkin lymphoma (HL); Mammalian target of rapamycin (mTOR); Notch; Tumour growth