Exploring metabolic interventions for CIN cancer therapy

Abstract

Chromosomal instability (CIN) has been established as one of the hallmarks of cancer, which is prevalent in most of the solid and advanced tumours. CIN enhances genetic heterogeneity in cancer cells. This heterogeneity provides selective advantages to cancer cells against the drugs and the therapies, which are linked to poor prognosis and relapse of cancer. Altered metabolism is another hallmark of cancer, which is being targeted for cancer therapy. In this thesis, I have discussed the therapeutic effect of targeting metabolism in CIN cells and CIN tumours. Chapter 1 is my introduction in which I have reviewed cancer, its therapy, CIN, its types, mechanisms, causes, and therapeutic targeting of CIN. I also review cancer metabolism, its targeting for the treatment, and targeting metabolism in CIN cells. Chapter 2 is a published review article about Drosophila being a model for CIN. In this article I have discussed different CIN models and their limitations, then I described Drosophila as a model for CIN studies. I later discussed different Drosophila CIN model systems which have been studied to understand CIN and cancer. As Drosophila has been extensively studied for CIN and cancer therapy, our lab has focused on targeting CIN cells in Drosophila. In an earlier study (Shaukat et al, 2012) it was found metabolic candidates such as Pas kinase and phosphofructokinase could be crucial for CIN cell survival. Chapter 3 is a further screening of metabolic candidates. We found few potential targets from all the major metabolic pathways whose knock down can specifically kill CIN cells. It was found, mitochondrial activity and oxidative stress was high which induced DNA damage and apoptosis in CIN cells targeted by these metabolic alterations. In chapter 4, I discuss the application of the selected candidates on CIN tumours. We further explain how one of my metabolic candidates stopped the tumour growth. This chapter also discusses the mechanism of ROS (reactive oxygen species) production and implications of high NADH levels in CIN cells, which was deficient in our earlier studies. Chapter 5 is my discussion in which I have collectively discussed my results, the significant of my work, my current model, and future directions. In appendix 1 I have presented a published review article on the role of JNK in response to oxidative DNA damage. This chapter encompasses activation of JNK by ROS, outcomes of JNK in response to ROS. Appendix 2 has figures for SOX drug and ovary numbers of the hosts.