靶向雌激素相关受体以缓解肿瘤耐药：连接细胞能量代谢的全面策略

靶向雌激素相关受体以缓解肿瘤耐药：连接细胞能量代谢的全面策略

Targeting estrogen-related receptors to mitigate tumor resistance: A comprehensive approach to bridging cellular energy metabolism

作者:Yuan Ren, Xiaodan Mao, Wenyu Lin, Yi Chen, Rongfeng Chen, Pengming Sun

期刊:BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER

摘要

人类与恶性肿瘤之间的斗争持续进行，经典化疗、放疗、靶向药物、内分泌治疗和免疫治疗不断取得新进展。然而，肿瘤细胞可能对这些治疗方法产生原发性或继发性耐药，成为影响患者预后和复发的主要因素。雌激素相关受体（ERRs）属于核受体超家族，主要调节葡萄糖、脂质和氨基酸代谢，作为细胞内能量代谢的核心枢纽。ERRs不仅介导胰岛素抵抗，还参与多种肿瘤的药物耐药机制，包括乳腺癌、骨肉瘤、子宫内膜癌、肺癌和肝癌，甚至调节放疗和免疫治疗的耐药性。它们主要通过细胞内的代谢重编程，影响线粒体能量代谢，调控胆固醇、谷氨酰胺和乳酸等代谢物，或通过影响其他信号通路和免疫微环境，抵抗肿瘤治疗。ERRs作为解决肿瘤耐药困境的潜在靶点，已有用于检测ERRα的电化学发光生物传感器，实现大规模、低成本的检测。此外，针对ERRs的靶向抑制剂在抑制癌细胞增殖和逆转耐药方面已显示出显著效果。本文回顾了ERRs在肿瘤耐药中的研究进展，为开发更有效的抗肿瘤策略提供重要参考。

Abstract

The war between humanity and malignant tumors has been ongoing, with continuous advancements in classic chemotherapy and radiotherapy regimens, targeted drugs, endocrine therapy, and immunotherapy. However, tumor cells can develop primary or secondary resistance to these treatment options, making the issue of tumor resistance a major factor affecting patient prognosis and leading to recurrence. Estrogen-related receptors (ERRs) are members of the nuclear receptor superfamily, primarily involved in regulating glucose, lipid, and amino acid metabolism, serving as a central hub for intracellular energy metabolism. ERRs not only mediate insulin resistance but also participate in the mechanisms of drug resistance in various tumors, including breast cancer, osteosarcoma, endometrial cancer, lung cancer, and liver cancer, and even mediate resistance to radiation and immunotherapy. They mainly resist tumor treatment methods through metabolic reprogramming within cells, affecting mitochondrial energy metabolism, regulating metabolites such as cholesterol, glutamine, and lactate, or other signaling pathways, or by influencing the immune microenvironment. ERRs are promising targets for addressing the dilemma of tumor resistance. Currently, electrochemical luminescence biosensors for detecting ERRα in bodily fluids have been developed, making large-scale, low-cost detection of ERRα possible. Additionally, targeted inhibitors of ERRs have shown significant effects in suppressing cancer cell proliferation and reversing tumor resistance. This article reviews the research progress of ERRs in tumor resistance, providing important references for developing more effective anti-tumor treatment strategies.

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