title: Phospho-TCTP as a therapeutic target of Dihydroartemisinin for aggressive breast cancer cells.
abstract: Upregulation of Translationally Controlled Tumor Protein (TCTP) is associated with poorly differentiated aggressive tumors, including breast cancer, but the underlying mechanism(s) are still debated. Here, we show that in breast cancer cell lines TCTP is primarily localized in the nucleus, mostly in the phosphorylated form.The effects of Dihydroartemisinin (DHA), an anti-malaria agent that binds TCTP, were tested on breast cancer cells. DHA decreases cell proliferation and induces apoptotic cell death by targeting the phosphorylated form of TCTP. Remarkably, DHA enhances the anti-tumor effects of Doxorubicin in triple negative breast cancer cells resulting in an increased level of apoptosis. DHA also synergizes with Trastuzumab, used to treat HER2/neu positive breast cancers, to induce apoptosis of tumor cells.Finally, we present new clinical data that nuclear phospho-TCTP overexpression in primary breast cancer tissue is associated with high histological grade, increase expression of Ki-67 and with ER-negative breast cancer subtypes. Notably, phospho-TCTP expression levels increase in trastuzumab-resistant breast tumors, suggesting a possible role of phospho-TCTP as a new prognostic marker.In conclusion, the anti-tumor effect of DHA in vitro with conventional chemotherapeutics suggests a novel therapeutic strategy and identifies phospho-TCTP as a new promising target for advanced breast cancer.
authors.affiliation: Institute of Translational Pharmacology, National Research Council, Rome, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Lucibello
authors.affiliation: Institute of Translational Pharmacology, National Research Council, Rome, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Adanti
authors.affiliation: Medical Oncology Department, Pathology and Molecular Biology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Ester
authors.initials: E
authors.lastname: Antelmi
authors.affiliation: Institute of Translational Pharmacology, National Research Council, Rome, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Dezi
authors.affiliation: Institute of Translational Pharmacology, National Research Council, Rome, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Ciafrè
authors.affiliation: Medical Oncology Department, Pathology and Molecular Biology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Carcangiu
authors.affiliation: Institute of Translational Pharmacology, National Research Council, Rome, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Zonfrillo
authors.affiliation: Institute of Translational Pharmacology, National Research Council, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Nicotera
authors.affiliation: Medical Oncology Department, Pathology and Molecular Biology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Sica
authors.affiliation: Medical Oncology Department, Pathology and Molecular Biology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: De Braud
authors.affiliation: Institute of Translational Pharmacology, National Research Council, Rome, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Pierimarchi
mesh_terms: D000368:Aged; D000962:Antimalarials / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D037621:Artemisinins / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001940:Breast / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008875:Middle Aged; D060787:Neoplasm Grading; D010766:Phosphorylation / Q000187:drug effects; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068878:Trastuzumab / Q000494:pharmacology; D000090324:Tumor Protein, Translationally-Controlled 1
chemical_list: D000962:Antimalarials; D000970:Antineoplastic Agents; D037621:Artemisinins; D014408:Biomarkers, Tumor; D012333:RNA, Messenger; C000715647:TPT1 protein, human; D000090324:Tumor Protein, Translationally-Controlled 1; C039060:artenimol; D000068878:Trastuzumab
keywords: DHA; advanced breast cancer; combination therapy; phospho-TCTP; target therapy