Oncotarget

Research Papers:

Targeting the PTTG1 oncogene impairs proliferation and invasiveness of melanoma cells sensitive or with acquired resistance to the BRAF inhibitor dabrafenib

Simona Caporali, Ester Alvino, Pedro Miguel Lacal, Federica Ruffini, Lauretta Levati, Laura Bonmassar, Alessandro Scoppola, Paolo Marchetti, Simona Mastroeni, Gian Carlo Antonini Cappellini and Stefania D’Atri _

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Oncotarget. 2017; 8:113472-113493. https://doi.org/10.18632/oncotarget.23052

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Abstract

Simona Caporali1, Ester Alvino2, Pedro Miguel Lacal1, Federica Ruffini1, Lauretta Levati1, Laura Bonmassar1, Alessandro Scoppola3, Paolo Marchetti3,4, Simona Mastroeni5, Gian Carlo Antonini Cappellini3 and Stefania D’Atri1

1Laboratory of Molecular Oncology, Istituto Dermopatico dell’Immacolata-IRCCS, Rome, Italy

2Institute of Translational Pharmacology, National Council of Research, Rome, Italy

3Department of Oncology and Dermatological Oncology, Istituto Dermopatico dell’Immacolata-IRCCS, Rome, Italy

4UOC Oncologia, University of Rome “La Sapienza”, Rome, Italy

5Clinical Epidemiology Unit, Istituto Dermopatico dell’Immacolata-IRCCS, Rome, Italy

Correspondence to:

Stefania D’Atri, email: s.datri@idi.it

Keywords: melanoma; proliferation; invasion; PTTG1; dabrafenib

Received: August 03, 2017     Accepted: November 13, 2017     Published: December 09, 2017

ABSTRACT

The pituitary tumor transforming gene 1 (PTTG1) is implicated in tumor growth, metastasis and drug resistance. Here, we investigated the involvement of PTTG1 in melanoma cell proliferation, invasiveness and response to the BRAF inhibitor (BRAFi) dabrafenib. We also preliminary assessed the potential value of circulating PTTG1 protein to monitor melanoma patient response to BRAFi or to dabrafenib plus trametinib. Dabrafenib-resistant cell lines (A375R and SK-Mel28R) were more invasive than their drug-sensitive counterparts (A375 and SK-Mel28), but expressed comparable PTTG1 levels. Dabrafenib abrogated PTTG1 expression and impaired invasion of the extracellular matrix (ECM) in A375 and SK-Mel28 cells. In contrast, it affected neither PTTG1 expression in A375R and SK-Mel28R cells, nor ECM invasion in the latter cells, while further stimulated A375R cell invasiveness. Assessment of proliferation and ECM invasion in control and PTTG1-silenced A375 and SK-Mel28 cells, exposed or not to dabrafenib, demonstrated that the inhibitory effects of this drug were, at least in part, dependent on its ability to down-regulate PTTG1 expression. PTTG1-silencing also impaired proliferation and invasiveness of A375R and SK-Mel28R cells, and counteracted dabrafenib-induced stimulation of ECM invasion in A375R cells. Further experiments performed in A375R cells indicated that PTTG1-silencing impaired cell invasiveness through inhibition of MMP-9 and that PTTG1 expression and ECM invasion could be also reduced by the CDK4/6 inhibitor LEE011. PTTG1 targeting might, therefore, represent a useful strategy to impair proliferation and metastasis of melanomas resistant to BRAFi. Circulating PTTG1 also appeared to deserve further investigation as biomarker to monitor patient response to targeted therapy.


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