Pleiotropic roles, post-translational regulation and pharmacological targeting of NDRG1 in cancer

Abstract

The metastasis suppressor, NDRG1, is a promising therapeutic target for cancer treatment. In past decade, much of the research has elucidated the anti-oncogenic molecular functions of NDRG1 in cancer cells. However, studies in some cancer-types revealed that this protein may have a pro-oncogenic role, leading to cancer progression. Although the studies on NDRG1 have been performed in diverse cancer-types, there was no clear explanation for the pleiotropic roles of NDRG1. Furthermore, the link between post-translational modification of NDRG1, its sub-cellular localisation and cellular regulation was not fully understood. Therefore, the studies in this thesis aimed to elucidate the role of NDRG1 post-translational modification and cellular localisation on its pleiotropic effects in cancer. Further, cellular processing of NDRG1 protein and its potential functional interaction with the proto-oncogene, c-Met, were investigated. To summarise the contents of this thesis, the results from Chapter 3 demonstrated that phosphorylation and truncation of NDRG1 protein could dictate its cellular localisation, but does not play an important role in pleiotropy. Data from Chapter 4 showed that NDRG1 protein is regulated by both the autophay- and proteasome-mediated pathways, which generate different NDRG1 isoforms. Finally, studies in Chapter 5 demonstrated that the proto-oncogene, c-Met, is potently down-regulated by the NDRG1-inducing anti-cancer agents, di-2-pyridylketone thiosemicarzones in cancer cells via two mechanisms involving lysosomal degradation and intracellular shedding, but this effect was NDRG1-independent. The investigations in this dissertation broaden our understanding of NDRG1 pleiotropy and cellular processing in tumour cells, as well as uncovering the suppressive effect of the di-2-pyridylketone thiosemicarbazones on c-Met expression.