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RLIP76 Inhibition: A Promising Developmental Therapy for Neuroblastoma

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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.

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Abbreviations

4HNE:

4-hydroxy nonenal

cdc2:

Cyclin-dependent kinase 1 also known as CDK1 or cell division cycle protein 2 homolog

CDE:

Clathrin-dependent endocytosis

COSMIC:

Catalogue of somatic mutations in cancer

EGFR:

Epidermal growth factor receptor

GS-E:

Glutathione electrophile conjugates

GSH:

Glutathione

GST:

Glutathione S-transferase

Hsf1:

Heat shock transcription factor 1

IGFR:

Insulin growth factor receptor

LPO:

Lipid peroxidation

MAP:

Mercapturic acid pathway

MEFs:

Mouse embryonic fibroblasts

NB:

Neuroblastoma

PI3K:

Phosphatidylinositol 3-kinase

POB1:

Partner of RalBP1 or RLIP76

PUMA:

p53 upregulated mediator of apoptosis

RLIP76 (RALBP1):

A 76 kDa Ral-interacting protein

RLIP76−/− :

RLIP76 knockout homozygous mice

USP7:

Ubiquitin specific protease 7

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Acknowledgments and Disclosures

This work was supported in part by the Department of Defense grant (W81XWH-16-1-0641) and funds from the Perricone Family Foundation, Los Angeles, CA. Funding from the Beckman Research Institute of the City of Hope is also acknowledged. We apologize to all colleagues whose work we could not cite due to space constraints. No conflict of interest exists for any of the authors.

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Authors and Affiliations

  1. Department of Molecular Medicine, Comprehensive Cancer Center and National Medical Center, Beckman Research Institute of City of Hope, Duarte, California, 91010, USA

    Sharad S. Singhal, Lokesh Nagaprashantha, Jyotsana Singhal & David Horne

  2. University of Texas Health, San Antonio, Texas, 78229, USA

    Preeti Singhal

  3. University of California at San Diego, La Jolla, California, 92092, USA

    Sulabh Singhal

  4. Texas Tech University Health Sciences Center, Lubbock, Texas, 79430, USA

    Sanjay Awasthi

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  1. Sharad S. Singhal
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Singhal, S.S., Nagaprashantha, L., Singhal, P. et al. RLIP76 Inhibition: A Promising Developmental Therapy for Neuroblastoma. Pharm Res 34, 1673–1682 (2017). https://doi.org/10.1007/s11095-017-2154-y

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  • DOI: https://doi.org/10.1007/s11095-017-2154-y

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