Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.
Hunan Key Laboratory of Translational Radiation Oncology, Changsha, China.
Cancer Sci. 2023 Mar;114(3):822-836. doi: 10.1111/cas.15652. Epub 2022 Nov 29.
Metabolic reprogramming is the survival rule of tumor cells, and tumor cells can meet their high metabolic requirements by changing the energy metabolism mode. Metabolic reprogramming of tumor cells is an important biochemical basis of tumor malignant phenotypes. Ras-related C3 botulinum toxin substrate 1 (Rac1) is abnormally expressed in a variety of tumors and plays an important role in the proliferation, invasion, and migration of tumor cells. However, the role of Rac1 in tumor metabolic reprogramming is still unclear. Herein, we revealed that Rac1 was highly expressed in colon cancer tissues and cell lines. Rac1 promotes the proliferation, migration, and invasion of colon cancer cells by upregulating SOX9, which as a transcription factor can directly bind to the promoters of HK2 and G6PD genes and regulate their transcriptional activity. Rac1 upregulates the expression of SOX9 through the PI3K/AKT signaling pathway. Moreover, Rac1 can promote glycolysis and the activation of the pentose phosphate pathway in colon cancer cells by mediating the axis of SOX9/HK2/G6PD. These findings reveal novel regulatory axes involving Rac1/SOX9/HK2/G6PD in the development and progression of colon cancer, providing novel promising therapeutic targets.
代谢重编程是肿瘤细胞的生存法则，肿瘤细胞可以通过改变能量代谢模式来满足其高代谢需求。肿瘤细胞的代谢重编程是肿瘤恶性表型的重要生化基础。Ras 相关 C3 肉毒杆菌毒素底物 1（Rac1）在多种肿瘤中异常表达，在肿瘤细胞的增殖、侵袭和迁移中发挥重要作用。然而，Rac1 在肿瘤代谢重编程中的作用尚不清楚。本研究揭示 Rac1 在结肠癌组织和细胞系中高表达。Rac1 通过上调 SOX9 促进结肠癌细胞的增殖、迁移和侵袭，SOX9 作为转录因子可以直接结合 HK2 和 G6PD 基因的启动子，调节其转录活性。Rac1 通过 PI3K/AKT 信号通路上调 SOX9 的表达。此外，Rac1 通过介导 SOX9/HK2/G6PD 轴促进结肠癌细胞中的糖酵解和戊糖磷酸途径的激活。这些发现揭示了 Rac1/SOX9/HK2/G6PD 在结肠癌发生发展中的新的调节轴，为结肠癌的治疗提供了新的有希望的治疗靶点。
