RLIP: A necessary transporter protein for translating oxidative stress into pro-obesity and pro-carcinogenic signaling

Previously, we showed that knockout mice homozygous for deficiency of the mercapturic acid pathway (MAP) transporter protein, RLIP (RLIP^?/?), are resistant to chemical carcinogenesis, inflammation, and metabolic syndrome (MetS). We also found that RLIP^?/? mice are highly resistant to obesity caused by a high-fat diet (HFD). Interestingly, these studies showed that kinase, cytokine, and adipokine signaling that are characteristics of obesity were blocked despite the presence of increased oxidative stress in RLIP^?/? mice. The deficiencies in obesity-inducing kinase, cytokine, and adipokine signaling were attributable to a lack of clathrin-dependent endocytosis (CDE), a process that is severely deficient in RLIP^?/? mice. Because CDE is also necessary for carcinogenic signaling through EGF, WNT, TGFβ and other cancer-specific peptide hormones, and because RLIP^?/? mice are cancer-resistant, we reasoned that depletion of RLIP by an antisense approach should cause cancer regression in human cancer xenografts. This prediction has been confirmed in studies of xenografts from lung, kidney, prostate, breast, and pancreatic cancers and melanoma. Because these results suggested an essential role for RLIP in carcinogenesis, and because our studies have also revealed a direct interaction between p53 and RLIP, we reasoned that if RLIP played a central role in carcinogenesis, that development of lymphoma in p53^?/? mice, which normally occurs by the time these mice are 6 months old, could be delayed or prevented by depleting RLIP. Recent studies described herein have confirmed this hypothesis, showing complete suppression of lymphomagenesis in p53^?/? mice treated with anti-RLIP antisense until the age of 8 months. All control mice developed lymphoma in the thymus or testis as expected. These findings lead to a novel paradigm predicting that under conditions of increased oxidative stress, the consequent increased flux of metabolites in the MAP causes a proportional increase in the rate of CDE. Because CDE inhibits insulin and TNF signaling but promotes EGF, TGFβ, and Wnt signaling, our model predicts that chronic stress-induced increases in RLIP (and consequently CDE) will induce insulin-resistance and enhance predisposition to cancer. Alternatively, generalized depletion of RLIP would antagonize the growth of malignant cells, and concomitantly exert therapeutic insulin-sensitizing effects. Therefore, this review focuses on how targeted depletion or inhibition of RLIP could provide a novel target for treating both obesity and cancer.