文献类型：期刊文献

英文题名：Multi-omics analysis defines 5-fluorouracil drug resistance in 3D HeLa carcinoma cell model

作者：Wang, Lin[1];Wang, Xueting[1];Wang, Tong[1];Zhuang, Yingping[1];Wang, Guan[1,2]

机构：[1]East China Univ Sci & Technol, State Key Lab Bioreactor Engn, Shanghai, Peoples R China;[2]East China Univ Sci & Technol, Qingdao Innovat Inst, Shanghai, Peoples R China

年份：2021

卷号：8

期号：1

外文期刊名：BIORESOURCES AND BIOPROCESSING

收录：;EI(收录号：20224513082790);WOS:【SCI-EXPANDED(收录号:WOS:000733741000001)】；

基金：This work was financially sponsored by State Key Laboratory of Bioreactor Engineering, Scientific Research Think Tank of Biological Manufacturing Industry in Qingdao (QDSWZK202004), the Fundamental Research Funds for the Central Universities (Grant No. JKJ01211515) and the 111 project (Grant No. B18022).

语种：英文

外文关键词：Drug resistance mechanism; HeLa carcinoma cells; Multicellular tumor spheroid; Multi-omics analysis; Preclinical evaluation; Tumor metabolism

摘要：Cervical cancer is a serious health problem in women around the globe. However, the use of clinical drug is seriously dampened by the development of drug resistance. Efficient in vitro tumor model is essential to improve the efficiency of drug screening and the accuracy of clinical application. Multicellular tumor spheroids (MTSs) can in a way recapitulates tumor traits in vivo, thereby representing a powerful transitional model between 2D monolayer culture and xenograft. In this study, based on the liquid overlay method, a protocol for rapid generation of the MTSs with uniform size and high reproducibility in a high-throughput manner was established. As expected, the cytotoxicity results showed that there was enhanced 5-fluorouracil (5-FU) resistance of HeLa carcinoma cells in 3D MTSs than 2D monolayer culture with a resistance index of 5.72. In order to obtain a holistic view of the molecular mechanisms that drive 5-FU resistance in 3D HeLa carcinoma cells, a multi-omics study was applied to discover hidden biological regularities. It was observed that in the 3D MTSs mitochondrial function-related proteins and the metabolites of the tricarboxylic acid cycle (TCA 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 were significant, mainly in the heat shock protein family, with the up-regulation of protein folding function in endoplasmic reticulum (ER), which promoted the maintenance of ER homeostasis in the 3D MTSs. In addition, at the transcript and protein level, the expression of extracellular matrix (ECM) proteins (e.g., laminin and collagen) were up-regulated in the 3D MTSs, which enhanced the physical barrier of drug penetration. Summarizing, this study formulates a rapid, scalable and reproducible in vitro model of 3D MTS for drug screening purposes, and the findings establish a critical role of glycolytic metabolism, ER hemostasis and ECM proteins expression profiling in tumor chemoresistance of HeLa carcinoma cells towards 5-FU.