Role of LDL cholesterol and annexin A6 for cancer cell growth and progression
Access status:
Open Access
Type
ThesisThesis type
Doctor of PhilosophyAuthor/s
Wahba, MohamedAbstract
The increased demand for cholesterol to support cancer growth and progression is often
associated with elevated uptake of cholesterol from low density lipoproteins (LDL). Once
endocytosed, LDL-cholesterol then needs to be delivered from late endosomes/lysosomes
(LE/Lys) ...
See moreThe increased demand for cholesterol to support cancer growth and progression is often associated with elevated uptake of cholesterol from low density lipoproteins (LDL). Once endocytosed, LDL-cholesterol then needs to be delivered from late endosomes/lysosomes (LE/Lys) to other cellular sites to promote proliferation and metastatic behaviour. Yet, in oncogenic settings, the cholesterol transporters and molecular machinery in LE/Lys that endorse this process are not fully understood. In Chapter 1, the impact of inhibiting late endosomal cholesterol export on aggressive cancer cell behaviour was addressed. Therefore, we depleted the major cholesterol transporter in LE/Lys (Niemann Pick Type C1, NPC1) with stable siRNA-mediated gene knockdown in human A431 squamous epithelial cells, a well-established cancer model with metastatic features. The NPC1- depleted A431 cell line displayed strong cholesterol accumulation in LE/Lys similar to recognized NPC1 mutant cell lines and were suitable for experiments assessing motility and invasive behaviour. Indeed, cholesterol accumulation in NPC1-depleted A431 cells correlated with significantly reduced cell migration in wound healing assays. Moreover, after tail vein injection, the number of tumors in the lung derived from NPC1-depleted A431 cells were strongly reduced, suggesting that inability to distribute late endosomal cholesterol interferes with the invasive potential of A431 cells in vivo.
See less
See moreThe increased demand for cholesterol to support cancer growth and progression is often associated with elevated uptake of cholesterol from low density lipoproteins (LDL). Once endocytosed, LDL-cholesterol then needs to be delivered from late endosomes/lysosomes (LE/Lys) to other cellular sites to promote proliferation and metastatic behaviour. Yet, in oncogenic settings, the cholesterol transporters and molecular machinery in LE/Lys that endorse this process are not fully understood. In Chapter 1, the impact of inhibiting late endosomal cholesterol export on aggressive cancer cell behaviour was addressed. Therefore, we depleted the major cholesterol transporter in LE/Lys (Niemann Pick Type C1, NPC1) with stable siRNA-mediated gene knockdown in human A431 squamous epithelial cells, a well-established cancer model with metastatic features. The NPC1- depleted A431 cell line displayed strong cholesterol accumulation in LE/Lys similar to recognized NPC1 mutant cell lines and were suitable for experiments assessing motility and invasive behaviour. Indeed, cholesterol accumulation in NPC1-depleted A431 cells correlated with significantly reduced cell migration in wound healing assays. Moreover, after tail vein injection, the number of tumors in the lung derived from NPC1-depleted A431 cells were strongly reduced, suggesting that inability to distribute late endosomal cholesterol interferes with the invasive potential of A431 cells in vivo.
See less
Date
2023Licence
Copyright All Rights ReservedRights statement
The author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.Faculty/School
Faculty of Medicine and Health, The University of Sydney School of PharmacyAwarding institution
The University of SydneyShare