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

Anita Thyagarajan,Jeremiah Saylae,Ravi P Sahu

doi:10.18632/oncotarget.18326

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.

Highlights

Malignant melanoma is the most aggressive type of skin cancer that contributes about 80% of skin-cancerrelated deaths leading to over 9000 annual mortality in the United States [1]
Aspirin inhibits the survival of murine melanoma cells via inducing apoptosis Given our studies demonstrating the role of platelet-activating factor (PAF)-R signaling in melanoma tumor growth [16,17,18,19,20], we first tested the involvement of platelet-activating factorreceptor (PAF-R) pathway in acetylsalicylic acid (ASA)-induced effects
These findings indicate that ASA-induced effects bypass cellular-PAF-R signaling in melanoma cells and these effects are not specific to murine melanoma

Summary

Introduction

Malignant melanoma is the most aggressive type of skin cancer that contributes about 80% of skin-cancerrelated deaths leading to over 9000 annual mortality in the United States [1]. Immunotherapy strategies have shown the most promise as the immune responses are critical for the eradication of melanoma [7,8]. Most standard therapies for cancers including melanoma act as potent pro-oxidative stressors by which they eradicate tumor cells as one of the potent mechanisms [9,10,11,12,13]. PAF-R activation by pro-oxidative stressors including the therapeutic agents, augment the growth and impede cancer therapy efficacy in experimental murine melanoma models in a process blocked by cyclooxygenase type 2 (COX-2) inhibitors [16,17,18,19]. Cyclooxygenases (COX) enzyme catalyzes the conversion of arachidonic acid to prostaglandins (PGs) [24,25,26]

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Results

Conclusion