Phospho-TCTP as a therapeutic target of Dihydroartemisinin for aggressive breast cancer cells

// Maria Lucibello 1 , Sara Adanti 1 , Ester Antelmi 2 , Dario Dezi 1 , Stefania Ciafre 1 , Maria Luisa Carcangiu 2 , Manuela Zonfrillo 1 , Giuseppe Nicotera 1 , Lorenzo Sica 2 , Filippo De Braud 2 , Pasquale Pierimarchi 1 1 Institute of Translational Pharmacology, National Research Council, Rome, Italy 2 Medical Oncology Department, Pathology and Molecular Biology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy Correspondence to: Maria Lucibello, e-mail: maria.lucibello@ift.cnr.it Keywords: Advanced breast cancer, phospho-TCTP, DHA, target therapy, combination therapy Received: September 22, 2014      Accepted: December 16, 2014      Published: March 12, 2015 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.