Oncotarget

Research Papers:

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

Luisa Paris, Franca Podo _, Francesca Spadaro, Laura Abalsamo, Maria Elena Pisanu, Alessandro Ricci, Serena Cecchetti, Luisa Altabella, Maria Buoncervello, Ludmila Lozneanu, Marina Bagnoli, Carlo Ramoni, Silvana Canevari, Delia Mezzanzanica, Egidio Iorio and Rossella Canese

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Oncotarget. 2017; 8:55022-55038. https://doi.org/10.18632/oncotarget.18992

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Abstract

Luisa Paris1,*, Franca Podo1,*, Francesca Spadaro2, Laura Abalsamo1, Maria Elena Pisanu1, Alessandro Ricci1, Serena Cecchetti1, Luisa Altabella1, Maria Buoncervello2, Ludmila Lozneanu3,4, Marina Bagnoli3, Carlo Ramoni1, Silvana Canevari3, Delia Mezzanzanica3, Egidio Iorio1,* and Rossella Canese1,*

1Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, 00161, Roma, Italy

2Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161, Roma, Italy

3Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milano, Italy

4Department 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: [email protected], [email protected]

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.


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PII: 18992