Phospho-TCTP as a therapeutic target of Dihydroartemisinin for aggressive breast cancer cells
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Maria Lucibello1, Sara Adanti1, Ester Antelmi2, Dario Dezi1, Stefania Ciafrè1, Maria Luisa Carcangiu2, Manuela Zonfrillo1, Giuseppe Nicotera1, Lorenzo Sica2, Filippo De Braud2, Pasquale Pierimarchi1
1Institute of Translational Pharmacology, National Research Council, Rome, Italy
2Medical Oncology Department, Pathology and Molecular Biology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Maria Lucibello, e-mail: firstname.lastname@example.org
Keywords: Advanced breast cancer, phospho-TCTP, DHA, target therapy, combination therapy
Received: September 22, 2014 Accepted: December 16, 2014 Published: March 12, 2015
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.
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