Understanding the molecular mechanisms that underlie the anti-cancer activity of the metastasis suppressor, NDRG1 in the treatment of cancer.

Abstract

Pancreatic cancer is an aggressive disease that continues to be associated with low survival rates, therefore there is a need for more targeted therapies. This thesis sought to elucidate the mechanism of action of a well-known metastasis suppressor, N-myc downstream regulated gene 1 (NDRG1). In addition, this thesis proposed a promising therapeutic strategy, exploring the use of a potent new class of di-2-pyridylketone thiosemicarbazone anti-cancer agents that up-regulate NDRG1. NDRG1 can suppress the epithelial mesenchymal transition, a key step in metastasis. We demonstrated that NDRG1 inhibited the oncogenic effects of transforming growth factor-β (TGF-β) in PANC-1 pancreatic cancer cells, mediated by the reduction of three transcriptional repressors of E-cadherin, namely SNAIL, SLUG, and ZEB1. Interestingly, NDRG1 also comprehensively inhibited oncogenic NF-κB signalling at multiple sites. The novel di-2-pyridylketone thiosemicarbazones, down-regulated the E-cadherin repressors in-vitro and in-vivo, demonstrating their marked potential. Furthermore, considering the broad effects of NDRG1 on a plethora of oncogenic signaling, it was shown that NDRG1 inhibited the ErbB family of receptors including the epidermal growth factor (EGFR), which are master regulators of oncogenesis, in order to elicit its reported and vast effects. This was mediated by the ability of NDRG1 to promote the tumour suppressor, MIG6 in order to disrupt its signalling, and cause its degradation. Collectively, these findings have expanded our knowledge of the mechanisms that underpin the molecular roles of NDRG1. Through the implementation of the novel di-2-pyridylketone thiosemicarbazones, this thesis has highlighted that targeting NDRG1 has tremendous therapeutic potential for the treatment of cancer.