Fructose, the most common food sweetener, is widely used in processed sugary beverages, candies, and baked goods. Excessive fructose intake is closely associated with metabolic diseases like obesity, diabetes, and fatty liver. Epidemiological studies have also shown that excessive fructose consumption increases the risk of colorectal cancer. However, the mechanisms of fructose in the progression of colorectal cancer remain unclear.

Recently, a research team of Professor Piao Hailong from the Dalian Institute of Chemical Physics (DICP) of the Chinese Academy of Sciences (CAS), in collaboration with the research teams of Professor Bu Pengcheng from CAS’s Institute of Biophysics, and Professor Shen Xian from Wenzhou Medical University, have uncovered a new mechanism by which fructose inhibited the polarization of M1-type tumor-associated macrophages (M1-like TAMs), thereby promoting colorectal cancer development. This study was published in Cell Metabolism.

Fructose promotes the progression of colorectal cancer through inhibition of the polarization of M1-like tumor-associated macrophages.[IMAGE: YAN HUIWEN]

The researchers found that, in contrast to hepatocytes (primary cells for fructose metabolism), the metabolic rate of fructose in macrophages was significantly slower. Using 13C-labeled fructose metabolic flux analysis and targeted metabolomics, they demonstrated that fructose likely inhibited the polarization of M1-like TAMs through hexokinase 2 (HK2) rather than its downstream metabolic products.

Furthermore, the researchers revealed that fructose promoted the interaction between HK2 and inositol 1,4,5-trisphophate receptor type 3 (ITPR3), a key protein component of Ca²⁺ transport channels in the endoplasmic reticulum. This interaction significantly reduced the formation of mitochondria-associated endoplasmic reticulum membranes (MAM) and decreased the concentration of calcium in the cytoplasm and mitochondria. Knocking out glucose transporter 5 (GLUT5) or supplementing a mutational HK2 in bone marrow-derived macrophages with reduced HK2 expression reversed the down-regulatory effects of fructose in MAM and calcium-level.

Additionally, the researchers observed that the interaction between HK2 and ITPR3 lowered calcium levels in mitochondria and cytoplasm, suppressing the activation of p38 mitogen-activated protein kinase (p38 MAPK) and signal transducer and activator of transcription 1 (STAT1), and NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. This inhibition ultimately blocked M1-like TAM polarization.

“Our study reveals a novel role of fructose as a signaling molecule that promotes colorectal cancer by inhibiting M1-like TAMs polarization,” said Professor Piao.

For more information, please contact:

Professor Piao Hailong

E-mail: hpiao@dicp.ac.cn

Dalian Institute of Chemical Physics,

Chinese Academy of Sciences

Source: Dalian Institute of Chemical Physics,

Chinese Academy of Sciences