Research Papers:

TWEAK activation of the non-canonical NF-κB signaling pathway differentially regulates melanoma and prostate cancer cell invasion

Cheryl L. Armstrong _, Rebeca Galisteo, Sharron A.N. Brown and Jeffrey A. Winkles

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Oncotarget. 2016; 7:81474-81492. https://doi.org/10.18632/oncotarget.13034

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Cheryl L. Armstrong1,2,3, Rebeca Galisteo1,2,3, Sharron A.N. Brown1,2,3, Jeffrey A. Winkles1,2,3

1Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA

2Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, USA

3Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA

Correspondence to:

Jeffrey A. Winkles, email: [email protected]

Keywords: TWEAK, Fn14, invasion, NF-κB, melanoma

Received: July 28, 2016    Accepted: October 14, 2016    Published: November 03, 2016


Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a multifunctional cytokine that binds with high affinity to a plasma membrane-anchored receptor named Fn14. Both TWEAK and Fn14 expression has been detected in human cancer tissue, and studies have shown that TWEAK/Fn14 signaling can promote either “pro-cancer” or “anti-cancer” cellular effects in vitro, depending on the cancer cell line under investigation. In this study, we engineered murine B16 melanoma cells to secrete high levels of soluble TWEAK and examined their properties. TWEAK production by B16 cells preferentially activated the non-canonical NF-κB signaling pathway and increased the expression of several previously described TWEAK-inducible genes, including Fn14. TWEAK overexpression in B16 cells inhibited both cell growth and invasion in vitro. The TWEAK-mediated reduction in B16 cell invasive capacity was dependent on activation of the non-canonical NF-κB signaling pathway. Finally, we found that this same signaling pathway was also important for TWEAK-stimulated human DU145 prostate cancer cell invasion. Therefore, even though TWEAK:Fn14 binding activates non-canonical NF-κB signaling in both melanoma and prostate cancer cells, this shared cellular response can trigger a very different downstream outcome (inhibition or stimulation of cell invasiveness, respectively).

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