Phosphatidylcholine-specific phospholipase C inhibition reduces HER2-overexpression, cell proliferation andin vivotumor growth in a highly tumorigenic ovarian cancer model

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// Luisa Paris 1, * , Franca Podo 1, * , Francesca Spadaro 2 , Laura Abalsamo 1 , Maria Elena Pisanu 1 , Alessandro Ricci 1 , Serena Cecchetti 1 , Luisa Altabella 1 , Maria Buoncervello 2 , Ludmila Lozneanu 3, 4 , Marina Bagnoli 3 , Carlo Ramoni 1 , Silvana Canevari 3 , Delia Mezzanzanica 3 , Egidio Iorio 1, * and Rossella Canese 1, * 1 Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, 00161, Roma, Italy 2 Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161, Roma, Italy 3 Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milano, Italy 4 Department of Histology, University of Medicine and Pharmacy “Grigore T. Popa”, 700115, Iasi, Romania * These authors contributed equally to this work Correspondence to: Franca Podo, email: franca.podo@alice.it , franca.podo@iss.it Keywords: ovarian cancer, HER2 overexpression, phosphatidylcholine-specific phospholipase C, magnetic resonance imaging, magnetic resonance spectroscopy Received: October 04, 2016 Accepted: June 19, 2017 Published: July 05, 2017 ABSTRACT Antagonizing the oncogenic effects of human epidermal growth factor receptor 2 (HER2) with current anti-HER2 agents has not yet yielded major progress in the treatment of advanced HER2-positive epithelial ovarian cancer (EOC). Using preclinical models to explore alternative molecular mechanisms affecting HER2 overexpression and oncogenicity may lead to new strategies for EOC patient treatment. We previously reported that phosphatidylcholine-specific phospholipase C (PC-PLC) exerts a pivotal role in regulating HER2 overexpression in breast cancer cells. The present study, conducted on two human HER2-overexpressing EOC cell lines - SKOV3 and its in vivo -passaged SKOV3.ip cell variant characterized by enhanced in vivo tumorigenicity - and on SKOV3.ip xenografts implanted in SCID mice, showed: a) about 2-fold higher PC-PLC and HER2 protein expression levels in SKOV3.ip compared to SKOV3 cells; b) physical association of PC-PLC with HER2 in non-raft domains; c) HER2 internalization and ca. 50% reduction of HER2 mRNA and protein expression levels in SKOV3.ip cells exposed to the PC-PLC inhibitor tricyclodecan-9-yl-potassium xanthate (D609); d) differential effects of D609 and trastuzumab on HER2 protein expression and cell proliferation; e) decreased in vivo tumor growth in SKOV3.ip xenografts during in vivo treatment with D609; f) potential use of in vivo magnetic resonance spectroscopy (MRS) and imaging (MRI) parameters as biomarkers of EOC response to PC-PLC inhibition. Overall, these findings support the view that PC-PLC inhibition may represent an effective means to target the tumorigenic effects of HER2 overexpression in EOC and that in vivo MR approaches can efficiently monitor its effects.