Sun Liang, Lu Ting, Jiang Linhua, Yao Huihui, Xu Qixuan, Sun Jie, Yang Xiaoqin, He Songbing, Zhu Xinguo
Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China.
Department of Ultrasound, The First Affiliated Hospital of Soochow University, Suzhou, China.
Cell Death Discov. 2025 Jan 5;10(1):489. doi: 10.1038/s41420-024-02249-z.
Metabolic reprogramming is considered one of the hallmarks of cancer in which cancer cells reprogram some of their metabolic cascades, mostly driven by the specific chemical microenvironment in cancer tissues. The altered metabolic pathways are increasingly being considered as potential targets for cancer therapy. In this view, Aldolase A (ALDOA), a key glycolytic enzyme, has been validated as a candidate oncogene in several cancers. The current study aimed to investigate the role of ALDOA in the initiation and development of colorectal cancer (CRC). In this study, we observed an elevated expression of ALDOA in human CRC tissues and a positive correlation of elevated ALDOA expression with tumor size, invasion depth, LNM, and TNM stage. Kaplan-Meier analysis revealed that elevated ALDOA levels correlated with a poor prognosis in CRC patients with stage I-III, whereas the prognosis tends to be favorable in patients with advanced CRC. In addition, loss of function and gain of function experiments showed that ALDOA promoted CRC cell proliferation and migration in vitro and in vivo. Mechanistically, high ALDOA expression inhibited AMP-activated protein kinase (AMPK) phosphorylation possibly through regulating cellular glycolysis or the formation of v-ATPase-regulator-AXIN/LKB1 complex, which led to Yes-associated protein (YAP) unphosphorylation and enhanced the proliferative and migratory potential of CRC cells. Finally, the positive correlation between ALDOA and YAP signaling was also confirmed in clinical CRC tissues and the public data. Herein, ALDOA was identified to be a new metabolic regulator of YAP that suppresses the activation of AMPK signaling. This could suggest a novel avenue for treating CRC by inhibiting both ALDOA and YAP signaling.
代谢重编程被认为是癌症的标志之一，其中癌细胞对其一些代谢级联进行重编程，这主要由癌组织中的特定化学微环境驱动。改变的代谢途径越来越被视为癌症治疗的潜在靶点。鉴于此，醛缩酶A（ALDOA）作为一种关键的糖酵解酶，已被证实是多种癌症中的候选癌基因。本研究旨在探讨ALDOA在结直肠癌（CRC）发生发展中的作用。在本研究中，我们观察到ALDOA在人CRC组织中表达升高，且ALDOA表达升高与肿瘤大小、浸润深度、淋巴结转移和TNM分期呈正相关。Kaplan-Meier分析显示，ALDOA水平升高与I-III期CRC患者的不良预后相关，而晚期CRC患者的预后往往较好。此外，功能丧失和功能获得实验表明，ALDOA在体外和体内均促进CRC细胞增殖和迁移。机制上，高ALDOA表达可能通过调节细胞糖酵解或v-ATP酶调节因子-AXIN/LKB1复合物的形成抑制AMP激活的蛋白激酶（AMPK）磷酸化，从而导致Yes相关蛋白（YAP）去磷酸化，增强CRC细胞的增殖和迁移潜能。最后，在临床CRC组织和公开数据中也证实了ALDOA与YAP信号之间的正相关。在此，ALDOA被确定为YAP的一种新的代谢调节因子，它抑制AMPK信号的激活。这可能为通过抑制ALDOA和YAP信号治疗CRC提供一条新途径。
