Liu Yanqing, Zhu Yongping, Gu Liwei, Li Kexin, Ma Ang, Liu Li, Meng Yuqing, Zhang Junzhe, Shen Shengnan, Shi Qiaoli, Liu Dandan, Zhang Xinwei, Zhang Shujie, Chai Xin, Gao Peng, Xing Jiale, Wang Yaxu, Chen Honglin, Liu Rui, Du Qingfeng, Liu Haitao, Dai Lingyun, Wang Jigang
State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
Department of Traditional Chinese Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China.
Int J Biol Sci. 2025 Jan 27;21(4):1619-1631. doi: 10.7150/ijbs.101921. eCollection 2025.
Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide and has become a recognized global health problem. Therefore, the search for new anti-CRC agents or the exploration of new effective drug targets for CRC therapy is urgent. Chloroquine (CQ) is a widely-used antimalarial drug and has shown anti-proliferative effects in CRC. However, the underlying mechanisms are not well understood, particularly as the direct targets of CQ have not been identified. In this study, choline kinase alpha (CHKA) and ATP-dependent 6-phosphofructokinase, muscle type (PFKM) were identified and verified as the binding targets of CQ. CQ specifically binds to CHKA, inhibits its expression and enzymatic activity, and downregulates the downstream phosphorylation of PI3K and AKT, thereby suppressing tumor cell proliferation and inducing apoptosis. CQ also binds to PFKM and inhibits its expression and activity, thereby blocking the Warburg effect. In addition, the downregulation of CHKA can decrease the expression of PFKM and inhibit its activity, thereby blocking the Warburg effect. These observations shed new light on the antitumor mechanisms of CQ and provide new evidence for the close relationship between the PI3K/AKT signaling pathway and the Warburg effect, providing new therapeutic targets for treating CRC.
结直肠癌（CRC）是全球癌症相关死亡的第二大主要原因，已成为一个公认的全球健康问题。因此，寻找新的抗CRC药物或探索用于CRC治疗的新的有效药物靶点迫在眉睫。氯喹（CQ）是一种广泛使用的抗疟药物，已显示出对CRC的抗增殖作用。然而，其潜在机制尚未完全了解，特别是CQ的直接靶点尚未确定。在本研究中，胆碱激酶α（CHKA）和肌肉型ATP依赖性6-磷酸果糖激酶（PFKM）被鉴定并验证为CQ的结合靶点。CQ特异性结合CHKA，抑制其表达和酶活性，并下调PI3K和AKT的下游磷酸化，从而抑制肿瘤细胞增殖并诱导凋亡。CQ还与PFKM结合并抑制其表达和活性，从而阻断瓦伯格效应。此外，CHKA的下调可降低PFKM的表达并抑制其活性，从而阻断瓦伯格效应。这些观察结果为CQ的抗肿瘤机制提供了新的见解，并为PI3K/AKT信号通路与瓦伯格效应之间的密切关系提供了新的证据，为治疗CRC提供了新的治疗靶点。
