Signaling pathways and novel genetic factors involved in modulation of cisplatin response in C. elegans

Abstract

Cancer is a major cause of mortality throughout the world. Despite the effort of the scientific community, plenty remains to understand about the biology or genetics of cancer. In solid tumors often as many as 90-99% of all cells are non-dividing. Therefore, it is challenging to fully understand the therapeutic effect of the drug using in vivo models where cells grow rapidly. Cisplatin is one of the most widely used chemotherapeutics known to treat different types of solid tumors. However, because of its primary ability to bind DNA and influence proliferating cells, its role in the non-dividing cells is often neglected. Nevertheless, a growing body of evidence shows that cisplatin has different cytoplasmic targets and can kill enucleated cells. Therefore, using C. elegans as a post-mitotic model we aimed to learn more about signaling pathways and genetic factors involved in the modulation of chemotherapeutic response on non-dividing cells. This thesis builds on our previous work showing that inactivation of ASNA-1 increases cisplatin sensitivity in C. elegans and reveals a previously undescribed impact of cisplatin in post-mitotic cells. More specifically, we have discovered a new mechanism by which cisplatin-induced ROS generation inactivates the cisplatin response function of ASNA-1 via its oxidation, which in turn perturbs the targeting of a tail-anchored protein to the endoplasmic reticulum membrane. This allowed us to separate clinically relevant ASNA-1 function in cisplatin sensitivity from insulin signaling. Next, analysis of tissue and genetic requirements of ASNA-1 allowed us to separate protein functions even further with a focus on growth, reproduction, and cisplatin response. Lastly, we showed that the PMK-1–ATF-7-regulated immunity pathway is required for cisplatin resistance and identified immune effectors as necessary for this response. In summary, using genetic and molecular analyses in C. elegans, we identified signaling pathways and novel genetic factors involved in the modulation of cisplatin response in post-mitotic cells with clear implications for strategies to refine and improve cisplatin cancer therapy.