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胆固醇代谢重编程在胰腺癌中的作用及靶向胆固醇代谢药物的应用

赵瑞丽^1,2, 李倩倩^1,2, 刘约瑟^1,2, 张娟^3,1,2,*

¹河南中医药大学第二临床医学院，郑州 450046；²河南省中医院(河南中医药大学第二附属医院)肿瘤科，郑州 450002；³河南中医药大学第一附属医院，郑州 450000

摘要

胰腺癌起病隐匿，缺乏有效的治疗方法，是预后最差的实体肿瘤之一，亟需探索新的治疗方向。代谢重编程是肿瘤的重要标志之一，处于恶劣肿瘤微环境中的胰腺癌细胞为了维持旺盛的代谢需求将胆固醇代谢全面上调，肿瘤相关成纤维细胞为癌细胞提供大量的脂质。胆固醇代谢重编程涉及胆固醇的合成、摄取、酯化、以及胆固醇相关代谢产物的一系列调整，与胰腺癌的增殖、侵袭、转移、耐药、免疫抑制等表型密切相关，抑制胆固醇代谢具有明显的抗肿瘤作用。本文从胰腺癌的高危因素、肿瘤相关成纤维细胞与癌细胞间的能量交互、细胞胆固醇代谢关键靶点的作用机制及其靶向药物，综述了胰腺癌胆固醇代谢的复杂性与重要性。胆固醇代谢具有严格的调控与反馈机制，单一靶点药物在临床应用中的效果并不明确，因此胆固醇代谢的多靶点疗法是胰腺癌治疗的新方向。

关键词： 胰腺癌; 胆固醇; 脂代谢; 代谢重编程

The role of cholesterol metabolism reprogramming in pancreatic cancer and the application of cholesterol-targeted metabolism drugs

ZHAO Rui-Li^1,2, LI Qian-Qian^1,2, LIU Yue-Se^1,2, ZHANG Juan^3,1,2,*

¹The Second Clinical Medical College, Henan University of Chinese Medicine, Zhengzhou 450046, China；²Department of Oncology, Henan Provincial Hospital of Traditional Chinese Medicine (The Second Affiliated Hospital of Henan University of Chinese Medicine), Zhengzhou 450002, China；³The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, China

Abstract

Pancreatic cancer has an insidious onset and lacks effective treatment methods, which is one of the tumors with the worst prognosis, so it is urgent to explore new treatment directions. Metabolic reprogramming is one of the important hallmarks of tumors. Pancreatic cancer cells in the harsh tumor microenvironment have comprehensively increased cholesterol metabolism in order to maintain strong metabolic needs, and cancer associated fibroblasts also provide cancer cells with a large amount of lipids. Cholesterol metabolism reprogramming involves the changes in the synthesis, uptake, esterification and metabolites of cholesterol, which are closely related to the proliferation, invasion, metastasis, drug resistance, and immunosuppression of pancreatic cancer. Inhibition of cholesterol metabolism has obvious anti-tumor effect. In this paper, the important effects and complexity of cholesterol metabolism in pancreatic cancer were comprehensively reviewed from perspectives of risk factors for pancreatic cancer, energy interaction between tumor-related cells, key targets of cholesterol metabolism and its targeted drugs. Cholesterol metabolism has a strict regulation and feedback mechanism, and the effect of single-target drugs in clinical application is not clear. Therefore, multi-target therapy of cholesterol metabolism is a new direction for pancreatic cancer treatment.

Key words: pancreatic cancer; cholesterol; lipid metabolism; metabolic reprogramming

收稿日期：　　录用日期：

通讯作者：张娟　　E-mail: cancer126@126.com

引用本文：

赵瑞丽, 李倩倩, 刘约瑟, 张娟. 胆固醇代谢重编程在胰腺癌中的作用及靶向胆固醇代谢药物的应用[J]. 生理学报 2023; 75 (3): 413-428.

ZHAO Rui-Li, LI Qian-Qian, LIU Yue-Se, ZHANG Juan. The role of cholesterol metabolism reprogramming in pancreatic cancer and the application of cholesterol-targeted metabolism drugs. Acta Physiol Sin 2023; 75 (3): 413-428 (in Chinese with English abstract).