Targeting of Ubiquitin E3 Ligase RNF5 as a Novel Therapeutic Strategy in Neuroectodermal Tumors

Cancers

Claudio Bruno¹  Elisa Principi¹  Lizzia Raffaghello¹  Cristina Pastorino²  Silvia Ravera³  Martina Morini⁴  Alessandra Eva⁴  Giovanna Bianchi⁵  Valeria Tomati⁶  Federico Zara⁶  Nicoletta Pedemonte⁶  Elvira Sondo⁶ 

[1] Center of Translational and Experimental Myology, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy;Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DI-NOGMI), University of Genoa, 16132 Genoa, Italy;Experimental Medicine Department, University of Genova, 16132 Genova, Italy;Laboratory of Molecular Biology, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy;Stem Cell Laboratory and Cell Therapy Center, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy;UOC Genetica Medica, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy;

关键词: RNF5;    neuroblastoma;    melanoma;    ubiquitin ligase;    endoplasmic reticulum associated protein degradation;   

DOI  :  10.3390/cancers14071802

来源: DOAJ

【 摘 要 】

RNF5, an endoplasmic reticulum (ER) E3 ubiquitin ligase, participates to the ER-associated protein degradation guaranteeing the protein homeostasis. Depending on tumor model tested, RNF5 exerts pro- or anti-tumor activity. The aim of this study was to elucidate the controversial role of RNF5 in neuroblastoma and melanoma, two neuroectodermal tumors of infancy and adulthood, respectively. RNF5 gene levels are evaluated in publicly available datasets reporting the gene expression profile of melanoma and neuroblastoma primary tumors at diagnosis. The therapeutic effect of Analog-1, an RNF5 pharmacological activator, was investigated on in vitro and in vivo neuroblastoma and melanoma models. In both neuroblastoma and melanoma patients the high expression of RNF5 correlated with a better prognostic outcome. Treatment of neuroblastoma and melanoma cell lines with Analog-1 reduced cell viability by impairing the glutamine availability and energy metabolism through inhibition of F₁F_o ATP-synthase activity. This latter event led to a marked increase in oxidative stress, which, in turn, caused cell death. Similarly, neuroblastoma- and melanoma-bearing mice treated with Analog-1 showed a significant delay of tumor growth in comparison to those treated with vehicle only. These findings validate RNF5 as an innovative drug target and support the development of Analog-1 in early phase clinical trials for neuroblastoma and melanoma patients.

【 授权许可】

Unknown