Multi-omics analysis defines 5-fluorouracil drug resistance in 3D HeLa
carcinoma cell model
Abstract
In this study, we formulate a rapid, scalable and reproducible in vitro
model of 3D MTS for drug screening purposes, and the cytotoxicity
results showed an enhanced 5-FU resistance of HeLa carcinoma cells in 3D
MTSs than 2D monolayer culture.In order to reveal the molecular
mechanisms that drive 5-FU resistance in 3D HeLa carcinoma cells, a
multi-omics study was applied to discover hidden biological
regularities. We found that in the 3D MTSs mitochondrial
function-related proteins and the metabolites of the tricarboxylic acid
cycle were significantly decreased, and the cellular metabolism was
shifted towards glycolysis. The differences in the protein synthesis,
processing, and transportation between 2D monolayer cultures and 3D MTSs
was significant, mainly in the heat shock protein family, with the
upregulation of protein folding function in endoplasmic reticulum, which
promoted the maintenance of ER homeostasis in the 3D MTSs. In addition,
at the transcript and protein level, the expression of extracellular
matrix proteins (e.g., laminin and collagen) were up-regulated in the 3D
MTSs, which enhanced the physical barrier of drug penetration.