Oncotarget

Research Papers:

Acetylsalicylic acid inhibits the growth of melanoma tumors via SOX2-dependent-PAF-R-independent signaling pathway

Anita Thyagarajan, Jeremiah Saylae and Ravi P. Sahu _

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Oncotarget. 2017; 8:49959-49972. https://doi.org/10.18632/oncotarget.18326

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Abstract

Anita Thyagarajan1, Jeremiah Saylae1 and Ravi P. Sahu1

1Department of Pharmacology and Toxicology, Boonshoft School of Medicine at Wright State University, Dayton, OH, USA

Correspondence to:

Ravi P. Sahu, email: ravi.sahu@wright.edu

Keywords: acetylsalicylic acid, melanoma, platelet-activating factor-receptor, prostaglandin F2 alpha, SOX2

Received: April 07, 2017    Accepted: May 06, 2017    Published: June 01, 2017

ABSTRACT

Acquired resistance to standard therapies remains a serious challenge, requiring novel therapeutic approaches that incorporate potential factors involved in tumor resistance. As cancers including melanoma express inflammatory cyclooxygenases generating prostaglandins implicated in tumor growth, we investigated mechanism of anti-inflammatory drug, acetylsalicylic acid (ASA) which has been shown to inhibit various tumor types, however, its effects against highly aggressive melanoma model are unclear. Given our reports that an activation of platelet-activating factor-receptor (PAF-R) augments the growth and impede efficacies of therapeutic agents in experimental melanoma, we also sought to determine if PAF-R mediates anti-melanoma activity of ASA. The current studies using stably PAF-R-positive (B16-PAFR) and negative (B16-MSCV) murine melanoma cells and PAF-R-expressing and deficient mice, demonstrate that ASA inhibits the in-vitro and in-vivo growth of highly aggressive B16F10 melanoma via bypassing tumoral or stromal PAF-R signaling. Similar ASA-induced effects in-vitro were seen in human melanoma and nasopharyngeal carcinoma cells positive or negative in PAF-R. Mechanistically, the ASA-induced decrease in cell survival and increase in apoptosis were significantly blocked by prostaglandin F2 alpha (PGF2α) agonists. Importantly, PCR array and qRT-PCR analysis of B16-tumors revealed significant downregulation of sry-related high-mobility-box-2 (SOX2) oncogene by ASA treatment. Interestingly, modulation of SOX2 expression by PGF2α agonists and upregulation by fibroblast growth factor 1 (FGF-1) rescued melanoma cells from ASA-induced decreased survival and increased apoptosis. Moreover, PGF2α-receptor antagonist, AL8810 mimics ASA-induced decreased melanoma cells survival which was significantly blocked by PGF2α and FGF-1. These findings indicate that ASA inhibits the growth of aggressive melanoma via SOX2-dependent-PAF-R-indepedent pathway.


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