Our laboratory is interested in the interface of cell signaling and oxidative stress metabolism and its role in carcinogenesis, stress-defense, drug-resistance, radiation-resistance and insulin-resistance.
RLIP76 (Ral Binding Protein, RalBP1) is a 76 kDa multifunctional protein associated with carcinogenesis, metastases, drug and radiation resistance. In association with Sanjay Awasthi, MD, our lab has worked on mapping the critical upstream and downstream regulators of RLIP76 in multiple phases of tumor progression and therapeutic response. RLIP76 is the major mercapturic acid pathway (MAP) transporter that functions in the ATP-dependent active efflux of glutathione (GSH) conjugates (GS-E) of products of lipid peroxidation like 4-Hydroxynonenal (4HNE) and chemotherapy drugs out of cells, thereby reducing the intracellular concentrations of toxic radicals and chemo drugs. Inhibition of the transport function of RLIP76 also reduces the signaling downstream of multiple kinase cascades like EGF, IGF and WNT pathways that are dependent on clathrin-dependent endocytosis (CDE). RLIP76 knockout mice are characteristically resistant to carcinogenesis. Inhibition of RLIP76 function and/depleting RLIP76 sensitizes multiple cancers to drug and radiation therapy.
Our lab has worked on the efficacy and mechanisms of the anticancer effects induced by 2’-hydroxyflavanone (2HF), didymin, and vicenin-2 in renal cancer, neuroblastoma and prostate cancers, respectively. These compounds have shown preliminary efficacy in targeting multiple kinases and tumor suppressors like EGF, IGF, PI3K, c-Myc, p53, and RB pathways along with promising effect on decreasing the levels of RLIP76, the MAP transporter. Current studies in breast cancer are focused on expanding the mechanistic basis and testing the efficacy at multiple critical stages of carcinogenesis, metastases and therapeutic resistance following administration of novel chemopreventive regimens.
We are working on COH-SR4 (a small molecule synthesized and named after Prof. Samuel Rahbar, MD, PhD, who actively guided and directed the initial stages of project) which has shown promising anticancer and antidiabetic effects in vitro and in vivo. COH-SR4 suppresses lipogenic genes like sterol regulatory element binding protein-1c (SREBF1), acetyl-Coenzyme A carboxylase (ACOACa), peroxisome proliferator-activated receptor gamma (PPARγ), fatty acid synthase (FASN), stearoyl-Coenzyme A desaturase 1 (SCD1), carnitine palmitoyltransferase 1a (CPT1a) and 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR), as well as gluconeogenic genes phosphoenolpyruvate carboxykinase 1 (PCK1) and glucose-6-phosphatase (G6PC) in the liver of obese mice.
COH-SR4 inhibits cell cycle kinases, decreases vimentin and fibronectin, and activates AMPK pathway while inhibiting cancer progression.
Mechanisms of action of COH-SR in lung cancer
We employ a sound combination of genetic, molecular biology and proteomic investigations in association with the City of Hope core facilities to specifically characterize the impact of candidate chemopreventive agents/chemotherapy drugs on the core signaling networks of importance in insulin resistance, oncogenic transformation and metastatic progression of cancers. This advanced and multi-disciplinary approach has made possible the integration of key essential and translational scientific parameters which expand the understanding of the molecular basis for anticancer effects of novel chemopreventive and/chemotherapeutic agents.