J Cancer 2020; 11(7):1657-1667. doi:10.7150/jca.38721 This issue

Research Paper

Knock down of Fas-Associated Protein with Death Domain (FADD) Sensitizes Osteosarcoma to TNFα-induced Cell Death

Mario G. Hollomon1,✉, LaNisha Patterson2, Janice Santiago-O'Farrill3, Eugenie S. Kleinerman4, Nancy Gordon4

1. Department of Biology, Texas Southern University, Houston, TX 77004
2. Department of Neuroscience, Cell Biology and Anatomy, The University of Texas Medical Branch, Galveston, TX 77555
3. Division of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054
4. Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054

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Citation:
Hollomon MG, Patterson L, Santiago-O'Farrill J, Kleinerman ES, Gordon N. Knock down of Fas-Associated Protein with Death Domain (FADD) Sensitizes Osteosarcoma to TNFα-induced Cell Death. J Cancer 2020; 11(7):1657-1667. doi:10.7150/jca.38721. Available from https://www.jcancer.org/v11p1657.htm

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Abstract

Fas-associated protein with death domain (FADD) was first identified for its role in linking death receptors to the apoptotic signaling pathway with subsequent cell death. Later studies reported non-apoptotic functions for FADD in normal cells and cancer cells. Non-apoptotic functions for FADD in osteosarcoma (OS) have not been reported. In this study, FADD protein expression was knocked down in human CCHOSD, LM7, and SaOS2 OS cell lines followed by assessment of sensitivity to TNFα- or TRAIL-induced cell death. Knock down of FADD significantly increased TNFα-induced cell death in LM7 and SaOS2 cell lines. The mode of TNFα-induced cell death was apoptosis and not necroptosis. Inhibition of nuclear factor kappa B (NFκB) in wildtype cells increased TNFα-induced cell death to similar levels observed in FADD knockdown cells, suggesting a role for FADD in NFκB pro-survival cell signaling. In addition, knock down of FADD increased SMAC mimetic-mediated TNFα-induced cell death in all cell lines studied. The results of this study indicate that FADD has a pro-survival function in OS following TNFα treatment that involves NFκB signaling. The results also indicate that the pro-survival function of FADD is associated with XIAP activity.

Keywords: FADD, osteosarcoma, TNFα, NFκB, XIAP