PhD defence X. (Xinyu) Zhou

Strategies and mechanisms for enhancing receptor-specific TRAIL-induced apoptosis

The thesis of Xinyu Zhou provides new strategies to enhance receptor-specific TRAIL-induced apoptosis for cancer treatment.

Zhou: “Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a promising candidate for cancer treatment due to its tumor specificity. TRAIL binds with death receptor (DR) 4 or 5 to initiate apoptotic signal transduction. In this thesis, we first introduced the protein engineering strategies of TNF ligands to target specific receptors and we reviewed the changes in the biological activity of some key ligands. In the experimental part, we worked with DR4-specific TRAIL variant 4C7 and DR5-specific TRAIL variant DHER to study combination treatments to overcome resistance. Artemisinin is an approved anti-malarial drug extracted from  Artemisia annua,  which has also been studied as an anti-tumor drug for decades. We showed that artemisinin-type drugs stimulate DR5-specific TRAIL-induced apoptosis by regulating wildtype P53 in colon cancer cells. Then, we investigated the possibility of performing this combination treatment in P53 mutated triple-negative breast cancer (TNBC) cells. The effectiveness of dihydroartemisinin (DHA) was improved by forming adducts with transferrin (TF). These DHA-TF adducts induce apoptosis and ferroptosis in TNBC cells. Meanwhile, they enhance TRAIL-induced apoptosis mainly through DR5 upregulation in a P53-independent and ROS-dependent manner. Based on our findings and literature research, we summarized the effects of artemisinin-type drugs on regulated cell death pathways, the combination strategies with biologics, and the nanocarriers for artemisinin delivery. Finally, the expression pattern of DR4 and DR5 and the influence of ionizing radiation on receptor-specific TRAIL in 2D and 3D spheroids were explored.”

Promotores Prof.dr. W.J. Quax