High glucose enhances Nε-(carboxymethyl)lysine (CML)-induced colorectal cancer progression via the ANO6/Smad2/3-E-cadherin signaling.

Colorectal cancer (CRC) is a leading cause of cancer deaths. Advanced glycation end products (AGEs) formed in hyperglycemia, particularly Nε-(carboxymethyl)lysine (CML), promote tumor progression, although its molecular mechanisms remain unclear. Anoctamin 6 (ANO6), a transmembrane protein involved in tumor proliferation, invasion, metastasis, and cell death. It may serve as a critical link between glucose metabolism and CRC progression. This study examined the effects of high glucose and CML on ANO6 expression in T84 CRC cells, and explored the role of ANO6 in cell proliferation and migration. Our findings demonstrate that high glucose and CML upregulated ANO6 expression (p = 0.002 and p = 0.03, respectively), which in turn reduced necrotic cell death through caspase-1 activation and promoted cell migration. Spheroid assays confirmed that high ANO6 expression produced compact spheroids with increased E-cadherin (p = 0.0001). CML further enhanced spheroid integrity and motility. Low glucose increased E-cadherin expression (p = 0.01) but decreased Smad2/3 activity (p = 0.04), while CML exposure restored Smad2/3 phosphorylation and enhanced migration. Taken together, high glucose and CML promote CRC progression through ANO6 upregulation, enhancing migration while suppressing pyroptosis. These findings identify ANO6 as a mechanistic link between metabolic dysregulation and EMT-driven metastasis, highlighting it as a promising therapeutic target. Targeting ANO6 may offer a novel therapeutic strategy for CRC, particularly in patients with hyperglycemia or diabetes-associated metabolic dysregulation.