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二肽基肽酶4调节二氢胆固醇还原酶24介导的胆固醇生物合成，以促进妊娠滋养细胞肿瘤细胞对甲氨蝶呤的耐药性。

DPP4 Regulates DHCR24-Mediated Cholesterol Biosynthesis to Promote Methotrexate Resistance in Gestational Trophoblastic Neoplastic Cells.

作者信息

Yuan Weijie, Yong Wenjing, Zhu Jing, Shi Dazun

机构信息

Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, China.

The Hunan Provincial Key Laboratory of Precision Diagnosis and Treatment for Gastrointestinal Tumor, Changsha, China.

出版信息

Front Oncol. 2021 Dec 2;11:704024. doi: 10.3389/fonc.2021.704024. eCollection 2021.

DOI:10.3389/fonc.2021.704024
PMID:34926239
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8675944/
Abstract

Metabolic reprogramming could promote cellular adaptation in response to chemotherapeutic drugs in cancer cells. Herein, we aimed to characterize the metabolomic profiles regulated by Dipeptidyl Peptidase 4 (DPP4) in methotrexate (MTX)-resistant gestational trophoblastic neoplastic (GTN) cells. A total of eighty metabolites were found to be commonly altered in DPP4-depleted JAR/MTX and JEG3/MTX cells. Cholesterol biosynthesis-related metabolites were markedly impacted by DPP4 knockdown in MTX-resistant sublines. Manipulation of DPP4 expression remarkably affected the level of cellular cholesterol in GTN cells. Our analysis also identified 24-Dehydrocholesterol Reductase (DHCR24) as a potential downstream effector of DPP4. Manipulation of DHCR24 expression affected cellular cholesterol level, reactive oxygen species (ROS) accumulation, and chemosensitivity to MTX in GTN cell models. In addition, over-expression of DHCR24 could markedly restore cellular cholesterol level and rescue cell survival in DPP4-depleted MTX-resistant GTN cells. Highly correlated expression of DPP4 and DHCR24 was observed in clinical GTN specimens. Further, DPP4 inhibitor sitagliptin effectively inhibited cholesterol biosynthesis, reduced DHCR24 expression and enhanced MTX-induced cytotoxicity and . In conclusion, our findings suggested that DPP4 might regulate DHCR24-mediated cholesterol biosynthesis to promote methotrexate resistance in GTN cells. Targeting DPP4/DHCR24 signaling might help to sensitize MTX-resistant GTN to MTX treatment.

摘要

代谢重编程可促进癌细胞对化疗药物产生细胞适应性。在此，我们旨在表征二肽基肽酶4（DPP4）在甲氨蝶呤（MTX）耐药的妊娠滋养细胞肿瘤（GTN）细胞中调节的代谢组学特征。在DPP4缺失的JAR/MTX和JEG3/MTX细胞中，共发现80种代谢物发生了共同改变。胆固醇生物合成相关代谢物在MTX耐药亚系中受到DPP4敲低的显著影响。DPP4表达的调控显著影响GTN细胞中的细胞胆固醇水平。我们的分析还确定24-脱氢胆固醇还原酶（DHCR24）是DPP4的潜在下游效应物。在GTN细胞模型中，DHCR24表达的调控影响细胞胆固醇水平、活性氧（ROS）积累和对MTX的化学敏感性。此外，DHCR24的过表达可显著恢复DPP4缺失的MTX耐药GTN细胞中的细胞胆固醇水平并挽救细胞存活。在临床GTN标本中观察到DPP4和DHCR24的高度相关表达。此外，DPP4抑制剂西他列汀有效抑制胆固醇生物合成，降低DHCR24表达并增强MTX诱导的细胞毒性。总之，我们的研究结果表明，DPP4可能调节DHCR24介导的胆固醇生物合成，以促进GTN细胞对甲氨蝶呤的耐药性。靶向DPP4/DHCR24信号通路可能有助于使MTX耐药的GTN对MTX治疗敏感。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e2c/8675944/fc9a9ca7c294/fonc-11-704024-g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e2c/8675944/a9d73bb360f5/fonc-11-704024-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e2c/8675944/8a8cb8a9860c/fonc-11-704024-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e2c/8675944/fc9a9ca7c294/fonc-11-704024-g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e2c/8675944/d4e8d8529ebb/fonc-11-704024-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e2c/8675944/a9d73bb360f5/fonc-11-704024-g006.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e2c/8675944/fc9a9ca7c294/fonc-11-704024-g008.jpg

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