Inhibition of RLIP76 Causes Complete Regression of Melanoma in Mice

Yogesh C. Awasthi, Ph.D.
University of Texas Medical Branch
R01ES12171

Background: RLIP76 is a glutathione-conjugate transport protein that helps cells defend themselves against toxins. It is a stress-responsive membrane protein and is implicated in the regulation of multiple signaling pathways. The clinical and physiological implications of RLIP76 extend to diverse processes, including stress resistance, chemotherapy drug resistance, radiation resistance, oxidative stress-induced disease and even insulin resistance. Studies have shown that inhibition or depletion of RLIP76 causes apoptosis in a number of cancer cell types.

Advance: To explore potential clinical impacts, these NIEHS-supported investigators compared the expression of RLIP76 in cancer and normal cell lines. These studies also included techniques to determine if depletion of RLIP76 would cause cancer-specific apoptosis. Expression of RLIP76 was found to be greater in malignant cells than non-malignant cells. Inhibition or depletion of the protein caused preferential apoptosis in a variety of malignant cells in culture. Most importantly, in a mouse melanoma model, administration of a single dose of RLIP76 antibodies, short interfering RNA, or antisense oligonucleotides caused complete tumor regression in 10 days.

Implications: These findings provide strong evidence that inhibition of RLIP76 through genetic techniques or by administration of antibodies may be a clinically relevant approach to treating cancer, especially melanoma. The dramatic results suggest advancing this technique to clinical practice. Further studies in melanoma and other cancer models and other susceptible cancer cell-lines would be needed to show the general applicability of these results prior to human clinical applications.

Citation: Singhal SS, Awasthi YC, Awasthi S. Regression of melanoma in a murine model by RLIP76 depletion. Cancer Res. 2006 Feb 15;66(4):2354-60.