Increased S1P induces S1PR2 internalization to blunt the sensitivity of colorectal cancer to 5-fluorouracil via promoting intracellular uracil generation  

作　　者：Yu-hang Zhang Shu-xiang Cui Sheng-biao Wan Shu-hua Wu Xian-jun Qu 

机构地区：[1]Department of Pharmacology,School of Basic Medical Sciences,Capital Medical University,Beijing 100069,China [2]Department of Toxicology and Sanitary Chemistry,School of Public Health,Capital Medical University,Beijing 100069,China [3]Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology,Key Laboratory of Marine Drugs,Ministry of Education,School of Medicine and Pharmacy,Ocean University of China,Qingdao 266100,China [4]Department of Pathology,Hospital of Binzhou Medical University,Binzhou 264003,China

出　　处：《Acta Pharmacologica Sinica》2021年第3期460-469,共10页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(91629303/81673449/81872884/81973350);the Beijing Natural Science Foundation and Scientific Research Program of Municipal Commission of Education(KZ201710025020/KZ201810025033)。

摘　　要：Sphingosine-1-phosphate(S1P),the backbone of most sphingolipids,activating S1P receptors(S1PRs)and the downstream G protein signaling has been implicated in chemoresistance.In this study we investigated the role of S1PR2 internalization in 5-fluorouracil(5-FU)resistance in human colorectal cancer(CRC).Clinical data of randomly selected 60 CRC specimens showed the correlation between S1PR2 internalization and increased intracellular uracil(P<0.001).Then we explored the regulatory mechanisms in CRC model of villin-S1PR2^(−/−)mice and CRC cell lines.We showed that co-administration of S1P promoted S1PR2 internalization from plasma membrane(PM)to endoplasmic reticulum(ER),thus blunted 5-FU efficacy against colorectal tumors in WT mice,compared to that in S1PR2^(−/−)mice.In HCT116 and HT-29 cells,application of S1P(10μM)empowered S1PR2 to internalize from PM to ER,thus inducing 5-FU resistance,whereas the specific S1PR2 inhibitor JTE-013(10μM)effectively inhibited S1P-induced S1PR2 internalization.Using Mag-Fluo-AM-labeling[Ca^(2+)]ER and LC-ESI-MS/MS,we revealed that internalized S1PR2 triggered elevating[Ca^(2+)]ER levels to activate PERK-eLF2α-ATF4 signaling in HCT116 cells.The activated ATF4 upregulated RNASET2-mediated uracil generation,which impaired exogenous 5-FU uptake to blunt 5-FU therapy.Overall,this study reveals a previously unrecognized mechanism of 5-FU resistance resulted from S1PR2 internalization-upregulated uracil generation in colorectal cancer,and provides the novel insight into the significance of S1PR2 localization in predicting the benefit of CRC patients from 5-FU-based chemotherapy.

关 键 词：colorectal cancer 5-FU resistance sphingosine-1-phosphate(SI P) S1PR2 internalization endoplasmic reticulum calcium([Ca^(2+)]ER) uracil generation JTE-013 

分 类 号：R96[医药卫生—药理学]