Abstract
While the TRAIL pathway represents a promising therapeutic target in melanoma, resistance to TRAIL-mediated apoptosis remains a barrier to its successful adoption. Since the Wnt/β-catenin pathway has been implicated in facilitating melanoma cell apoptosis, we investigated the effect of Wnt/β-catenin signaling on regulating the responses of melanoma cells to TRAIL. Co-treatment of melanoma cell lines with WNT3A-conditioned media and recombinant TRAIL significantly enhanced apoptosis compared to treatment with TRAIL alone. This apoptosis correlates with increased abundance of the pro-apoptotic proteins BCL2L11 and BBC3, and with decreased abundance of the anti-apoptotic regulator Mcl1. We then confirmed the involvement of the Wnt/β-catenin signaling pathway by demonstrating that siRNA-mediated knockdown of an intracellular β-catenin antagonist, AXIN1, or treating cells with an inhibitor of GSK-3 also enhanced melanoma cell sensitivity to TRAIL. These studies describe a novel regulation of TRAIL sensitivity in melanoma by Wnt/β-catenin signaling, and suggest that strategies to enhance Wnt/β-catenin signaling in combination with TRAIL agonists warrant further investigation.
Highlights
The incidence of melanoma has increased in recent decades, and it has become a major cause of cancer related morbidity and mortality
Our study demonstrates that activation of the Wnt/β-catenin pathway in melanoma significantly enhances apoptosis triggered by recombinant human TRAIL
An alternate marker of apoptosis, cleaved PARP, was measurably elevated when A375 cells were treated with WNT3A conditioned media (CM) in the presence of recombinant human TRAIL (rhTRAIL) compared with controls (Figure 1C)
Summary
The incidence of melanoma has increased in recent decades, and it has become a major cause of cancer related morbidity and mortality. Despite a growing understanding of the molecular pathogenesis of melanoma and the development of promising new therapies, overall survival with advanced/ metastatic disease remains poor [1]. Due to the limited efficacy of standard chemotherapies, intensive research has focused on the development of alternative approaches to promote melanoma cell death. TRAIL can potently induce apoptosis upon ligation of its cognate receptors Death Receptors 4 and 5 (encoded by DR4 and DR5, respectively) in many tumors including melanoma [2,3]. Melanoma cell lines and freshly isolated tumors are often resistant to TRAIL-mediated apoptosis, thereby limiting the potential efficacy of TRAIL agonists [5]
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