title: The DeISGylase USP18 limits TRAIL-induced apoptosis through the regulation of TRAIL levels: Cellular levels of TRAIL influences responsiveness to TRAIL-induced apoptosis.
abstract: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a promising molecule for anti-cancer therapies. Unfortunately, cancer cells frequently acquire resistance to rhTRAIL. Various co-treatments have been proposed to overcome apoptosis resistance to TRAIL. Here we show that downregulation of the deISGylase USP18 sensitizes cancer cells to rhTRAIL, whereas, elevate levels of USP18 inhibit TRAIL-induced apoptosis, in a deISGylase-independent manner. USP18 influences TRAIL signaling through the control of the IFN autocrine loop. In fact, cells with downregulated USP18 expression augment the expression of cellular TRAIL. Downregulation of cellular TRAIL abrogates the synergism between TRAIL and USP18 siRNA and also limits cell death induced by rhTRAIL. By comparing the apoptotic responsiveness to TRAIL in a panel of cancer cell lines, we have discovered a correlation between TRAIL levels and the apoptotic susceptibility to rhTRAIL, In cells expressing high levels of TRAIL-R2 susceptibility to rhTRAIL correlates with TRAIL expression. In conclusion, we propose that cellular TRAIL is an additional factor that can influence the apoptotic response to rhTRAIL.
authors.affiliation: Dipartimento di Scienze Mediche e Biologiche and MATI Center of Excellence; Università degli Studi di Udine; Udine, Italy.
authors.forename: Ivana
authors.initials: I
authors.lastname: Manini
authors.affiliation: Dipartimento di Scienze Mediche e Biologiche and MATI Center of Excellence; Università degli Studi di Udine; Udine, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sgorbissa
authors.affiliation: Dipartimento di Scienze Mediche e Biologiche and MATI Center of Excellence; Università degli Studi di Udine; Udine, Italy.
authors.forename: Harish
authors.initials: H
authors.lastname: Potu
authors.affiliation: Dipartimento di Scienze Mediche e Biologiche and MATI Center of Excellence; Università degli Studi di Udine; Udine, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Tomasella
authors.affiliation: Dipartimento di Scienze Mediche e Biologiche and MATI Center of Excellence; Università degli Studi di Udine; Udine, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Brancolini
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007372:Interferons / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D043222:Ubiquitin Thiolesterase
chemical_list: D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D007372:Interferons; D010450:Endopeptidases; C485560:USP18 protein, human; D043222:Ubiquitin Thiolesterase
keywords: IFN-α; IFNAR; TRAIL; TRAIL-R2; USP18; autocrine loop