Role of LDL cholesterol and annexin A6 for cancer cell growth and progression

Abstract

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) 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.