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RLIP76 Targeted Therapy for Kidney Cancer

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ABSTRACT

Despite recent improvements in chemotherapeutic approaches to treating kidney cancer, this malignancy remains deadly if not found and removed at an early stage of the disease. Kidney cancer is highly drug-resistant, which may at least partially result from high expression of transporter proteins in the cell membranes of kidney cells. Although these transporter proteins can contribute to drug-resistance, targeting proteins from the ATP-binding cassette transporter family has not been effective in reversing drug-resistance in kidney cancer. Recent studies have identified RLIP76 as a key stress-defense protein that protects normal cells from damage caused by stress conditions, including heat, ultra-violet light, X-irradiation, and oxidant/electrophilic toxic chemicals, and is crucial for protecting cancer cells from apoptosis. RLIP76 is the predominant glutathione-electrophile-conjugate (GS-E) transporter in cells, and inhibiting it with antibodies or through siRNA or antisense causes apoptosis in many cancer cell types. To date, blocking of RLIP76, either alone or in combination with chemotherapeutic drugs, as a therapeutic strategy for kidney cancer has not yet been evaluated in human clinical trials, although there is considerable potential for RLIP76 to be developed as a therapeutic agent for kidney cancer. In the present review, we discuss the mechanisms underlying apoptosis caused by RLIP76 depletion, the role of RLIP76 in clathrin-dependent endocytosis deficiency, and the feasibility of RLIP76-targeted therapy for kidney cancer.

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Abbreviations

4HNE:

4-hydroxy nonenal

CDE:

Clathrin-dependent endocytosis

GS-E:

Glutathione electrophile conjugates

GSH:

Glutathione

PI3K:

Phosphatidylinositol 3-kinase

RCC:

Renal cell carcinoma

RLIP76:

Ral-interacting protein

VEGF:

Vascular endothelial growth factor

VHL :

Von Hippel-Lindau

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ACKNOWLEDGMENTS AND DISCLOSURES

This work was supported by the National Institutes of Health grant (CA 77495) and funds from the Perricone Family Foundation, Los Angeles, CA. Funding from Beckman Research Institute of City of Hope is also acknowledged. We apologize to all colleagues whose work we could not cite due to space constraints.

Conflicts of interest

No conflict of interest exists for any of the authors.

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Authors and Affiliations

  1. Department of Diabetes & Metabolic Diseases Research, City of Hope, Comprehensive Cancer Center, Duarte, California, 91010, USA

    Sharad S. Singhal, Jyotsana Singhal, James Figarola & Sanjay Awasthi

  2. Department of Molecular Medicine, City of Hope, Comprehensive Cancer Center, Duarte, California, 91010, USA

    David Horne

  3. Department of Medical Oncology, Beckman Research Institute, City of Hope, Comprehensive Cancer Center, Duarte, California, 91010, USA

    Sanjay Awasthi

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  1. Sharad S. Singhal
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Correspondence to Sharad S. Singhal.

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Singhal, S.S., Singhal, J., Figarola, J. et al. RLIP76 Targeted Therapy for Kidney Cancer. Pharm Res 32, 3123–3136 (2015). https://doi.org/10.1007/s11095-015-1723-1

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