School of Food Science, Washington State University, Pullman, WA 99164, USA.
Pharmaceutical Sciences, Washington State University, Spokane, WA 99202, USA.
Genes (Basel). 2024 Jun 25;15(7):835. doi: 10.3390/genes15070835.
The incidence of colorectal cancer (CRC) is closely linked to metabolic diseases. Accumulating evidence suggests the regulatory role of AMP-activated protein kinase (AMPK) in cancer metabolic reprogramming. In this study, wild-type and AMPK knockout mice were subjected to azoxymethane-induced and dextran sulfate sodium (AOM/DSS)-promoted colitis-associated CRC induction. A stable AMPK-deficient Caco-2 cell line was also established for the mechanistic studies. The data showed that AMPK deficiency accelerated CRC development, characterized by increased tumor number, tumor size, and hyperplasia in AOM/DSS-treated mice. The aggravated colorectal tumorigenesis resulting from AMPK ablation was associated with reduced α-ketoglutarate production and ten-eleven translocation hydroxylase 2 (TET2) transcription, correlated with the reduced mismatch repair protein mutL homolog 1 (MLH1) protein. Furthermore, in AMPK-deficient Caco-2 cells, the mRNA expression of mismatch repair and tumor suppressor genes, intracellular α-ketoglutarate, and the protein level of TET2 were also downregulated. AMPK deficiency also increased hypermethylation in the CpG islands of in both colonic tissues and Caco-2 cells. In conclusion, AMPK deficiency leads to reduced α-ketoglutarate concentration and elevates the suppressive epigenetic modifications of tumor suppressor genes in gut epithelial cells, thereby increasing the risk of colorectal tumorigenesis. Given the modifiable nature of AMPK activity, it holds promise as a prospective molecular target for the prevention and treatment of CRC.
结直肠癌（CRC）的发病率与代谢疾病密切相关。越来越多的证据表明，AMP 激活蛋白激酶（AMPK）在癌症代谢重编程中起调节作用。在这项研究中，野生型和 AMPK 敲除小鼠接受了氧化偶氮甲烷诱导和葡聚糖硫酸钠（AOM/DSS）促进的结肠炎相关 CRC 诱导。还建立了稳定的 AMPK 缺陷 Caco-2 细胞系进行机制研究。数据显示，AMPK 缺陷加速了 CRC 的发展，表现在 AOM/DSS 处理的小鼠中肿瘤数量、肿瘤大小和增生增加。AMPK 缺失导致的结直肠肿瘤恶化与α-酮戊二酸产生减少和 ten-eleven 易位羟化酶 2（TET2）转录减少有关，与错配修复蛋白 mutL 同源物 1（MLH1）蛋白减少相关。此外，在 AMPK 缺陷的 Caco-2 细胞中，错配修复和肿瘤抑制基因的 mRNA 表达、细胞内α-酮戊二酸和 TET2 的蛋白水平也下调。AMPK 缺陷还增加了肠道组织和 Caco-2 细胞中基因的 CpG 岛的过度甲基化。总之，AMPK 缺陷导致α-酮戊二酸浓度降低，并增加了肠道上皮细胞中肿瘤抑制基因的抑制性表观遗传修饰，从而增加了结直肠肿瘤发生的风险。鉴于 AMPK 活性的可调节性，它有望成为预防和治疗 CRC 的有前途的分子靶点。
