Brief description:

N-myc downstream regulated gene 1 (NDRG1) is a well characterised and potent metastasis suppressor with a plethora of biological roles in the cell. Importantly, NDRG1 has been demonstrated to inhibit numerous oncogenic molecular pathways such as the PI3K/AKT , NF-κB and Wnt/β-catenin pathways that contribute to the development of cancer. Novel anti-cancer agents of the thiosemicarbazone class have been shown to inhibit cancer by upregulating NDRG1 expression, a unique and potentially more effective mechanism among existing anti-cancer agents in the treatment of cancer. This project attempts to elucidate for the first time a novel mechanism by which NDRG1 inhibits cancer involving the protein c-Cbl in pancreatic cancer cells.

The c-Cbl protein is an E3 ubiquitin ligase that initiates the degradation of proteins via proteasomal degradation. c-Cbl can inhibit oncogenic pathways in cancer by inducing the degradation of receptor tyrosine kinases such as epidermal growth factor receptor (EGFR). However, phosphorylation on Tyr731 and Tyr774 enables c-Cbl to recruit proteins such as the p85 phosphoinositide 3-kinase (PI3K) regulatory subunit and CT10 regulator of kinase (Crk) which subsequently promotes the PI3K/AKT and c-Met/Crk/JNK oncogenic pathways, respectively.

It is hypothesised that NDRG1 can inhibit the phosphorylation c-Cbl at these sites (Tyr731 and Tyr774), preventing the recruitment of p85 and Crk which may subsequently attenuate the PI3K/AKT and c-Met/Crk/JNK oncogenic pathways and result in a decrease in activation of downstream effectors such as AKT and JNK respectively in pancreatic cancer, leading to cancer inhibition. Novel anti-cancer agents of the thiosemicarbazone class, namely Dp44mT, DpC and recently developed PPP44mT, ZnPPP44mT, CuPPP44mT or Cu(PPP44mT)2 that induce NDRG1 expression may demonstrate a similar decrease c-Cbl phosphorylation on Tyr731 and Tyr774 which should inhibit these oncogenic pathways and support the proposed hypothesis. This study provides an insight into the molecular mechanisms of these innovative anti-cancer agents by dissecting the mechanisms of action of NDRG1 on c-Cbl and may unveil yet another mechanism of NDRG1 induced cancer inhibition to better understand the potential of this molecule for cancer treatment.