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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.
Highlights
The pituitary tumor transforming gene 1 (PTTG1), codes for a multifunctional protein involved in a variety of cellular processes [reviewed in 1–4]
In agreement with the results obtained with A375 and A375R cell lines, which were included in the invasion assays for comparison www.impactjournals.com/oncotarget (Figure 1B), SK-Mel-28R cells were about 2-fold more invasive than the corresponding dabrafenib-sensitive parental cells (Figure 1C)
While exposure to vascular endothelial growth factor (VEGF)-A caused an increase of extracellular matrix (ECM) invasion in both A375 and A375R cells, as previously reported [31], only SK-Mel28 cells responded to this cytokine (Figure 1C)
Summary
The pituitary tumor transforming gene 1 (PTTG1), codes for a multifunctional protein involved in a variety of cellular processes [reviewed in 1–4]. The PTTG1 protein plays a crucial role in the regulation of sister chromatid separation during mitosis [1,2,3,4]. It participates in DNA repair, apoptosis, senescence, metabolism and gene transcription [1,2,3,4]. PTTG1 is considered an oncogene [5, 6], and it is over-expressed in a variety of cancer cell lines as well as in a wide range of primary and metastatic tumors [1,2,3,4, 7,8,9,10,11,12], including melanoma [13]. The involvement of PTTG1 in tumor growth and metastasis is further highlighted by several studies showing that in cancer cell lines of various histological derivation ectopic expression of PTTG1 enhanced proliferation and/or invasiveness, whereas PTTG1 silencing produced opposite results [7, 8, 10,11,12, 17,18,19,20,21,22]
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