title: RLIP76 Inhibition: A Promising Developmental Therapy for Neuroblastoma.
abstract: Refractory and relapsed neuroblastoma (NB) present with significant challenges in clinical management. Though primary NBs largely with wild-type p53 respond well to interventions, dysfunctional signaling in the p53 pathways in a MYCN oncogene driven background is found in a number of children with NB. The p53-mutant NB is largely unresponsive to available therapies and p53-independent targeted therapeutics represents a vital need in pediatric oncology. We analyzed the findings on mercapturic acid pathway (MAP) transporter RLIP76, which has broad and critical effects on multiple pathways as essential for carcinogenesis, oxidative stress and drug-resistance, is over-expressed in NB. RLIP76 inhibition by antibodies or depletion by antisense causes apoptosis and sensitization to chemo-radiotherapy in many cancers. In addition, recent studies indicate that the interactions between p53, MYCN, and WNT regulate apoptosis resistance and protein ubiquitination. RLIP76 and p53 interact with each other and colocalize in NB cells. Targeted depletion/inhibition of RLIP76 causes apoptosis and tumor regression in NB irrespective of p53 status. In the present review, we discuss the mechanisms and the role of RLIP76 in oxidative stress, drug-resistance and clathrin-dependent endocytosis (CDE), and analyze the molecular basis for the role of RLIP76 targeted approaches in the context principal drivers of NB pathogenesis, progression and drug-resistance. The evidence from RLIP76 studies in other cancers, when taken in the context of our recent RLIP76 focused mechanistic studies in NB, provides strong basis for further characterization and development of RLIP76 targeted therapies for NB.
authors.affiliation: Department of Molecular Medicine, Comprehensive Cancer Center and National Medical Center, Beckman Research Institute of City of Hope, Duarte, California, 91010, USA. ssinghal@coh.org.
authors.forename: Sharad S
authors.initials: SS
authors.lastname: Singhal
authors.affiliation: Department of Molecular Medicine, Comprehensive Cancer Center and National Medical Center, Beckman Research Institute of City of Hope, Duarte, California, 91010, USA.
authors.forename: Lokesh
authors.initials: L
authors.lastname: Nagaprashantha
authors.affiliation: University of Texas Health, San Antonio, Texas, 78229, USA.
authors.forename: Preeti
authors.initials: P
authors.lastname: Singhal
authors.affiliation: University of California at San Diego, La Jolla, California, 92092, USA.
authors.forename: Sulabh
authors.initials: S
authors.lastname: Singhal
authors.affiliation: Department of Molecular Medicine, Comprehensive Cancer Center and National Medical Center, Beckman Research Institute of City of Hope, Duarte, California, 91010, USA.
authors.forename: Jyotsana
authors.initials: J
authors.lastname: Singhal
authors.affiliation: Texas Tech University Health Sciences Center, Lubbock, Texas, 79430, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Awasthi
authors.affiliation: Department of Molecular Medicine, Comprehensive Cancer Center and National Medical Center, Beckman Research Institute of City of Hope, Duarte, California, 91010, USA.
authors.forename: David
authors.initials: D
authors.lastname: Horne
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D001692:Biological Transport; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002648:Child; D002966:Clathrin / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004705:Endocytosis; D020690:GTPase-Activating Proteins / Q000037:antagonists & inhibitors*; D005978:Glutathione; D006801:Humans; D058990:Molecular Targeted Therapy; D009154:Mutation; D009364:Neoplasm Recurrence, Local; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D018384:Oxidative Stress; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D000906:Antibodies; D000970:Antineoplastic Agents; D002966:Clathrin; D020690:GTPase-Activating Proteins; C095637:RALBP1 protein, human; D016159:Tumor Suppressor Protein p53; D005978:Glutathione
keywords: RLIP76; chemotherapeutics; clathrin-dependent endocytosis; drug-resistance; glutathione-conjugate transport; neuroblastoma; p53