Abstract
Harmful effects of high fructose intake on health have been widely reported. Although fructose is known to promote cancer, little is known about the underlying mechanisms. Here, we found that fructose triggers breast cancer metastasis through the ketohexokinase-A signaling pathway. Molecular experiments showed that ketohexokinase-A, rather than ketohexokinase-C, is necessary and sufficient for fructose-induced cell invasion. Ketohexokinase-A-overexpressing breast cancer was found to be highly metastatic in fructose-fed mice. Mechanistically, cytoplasmic ketohexokinase-A enters into the nucleus during fructose stimulation, which is mediated by LRRC59 and KPNB1. In the nucleus, ketohexokinase-A phosphorylates YWHAH at Ser25 and the YWHAH recruits SLUG to the CDH1 promoter, which triggers cell migration. This study provides the effect of nutrition on breast cancer metastasis. High intake of fructose should be restricted in cancer patients to reduce the risk of metastasis. From a therapeutic perspective, the ketohexokinase-A signaling pathway could be a potential target to prevent cancer metastasis.
Highlights
Harmful effects of high fructose intake on health have been widely reported
We explored the metastogenic role of KHK-A in breast cancer because cell invasion in response to fructose was strongly shown in all three breast-cancer cell lines
MDA-MB-231 cells were morphologically altered with enhanced front–rear polarization and F-actin rearrangement (Fig. 1e and Supplementary Fig. 3c), which indicates that cells underwent the epithelial–mesenchymal transition (EMT)
Summary
Harmful effects of high fructose intake on health have been widely reported. fructose is known to promote cancer, little is known about the underlying mechanisms. We found that fructose triggers breast cancer metastasis through the ketohexokinase-A signaling pathway. Fructose-induced carcinogenesis is considered to be attributed to altered energy metabolism, increased oxidative stress, and inflammation[9,10,11]. The fructose flux is increased in pancreatic cancer cells, which accelerates nucleic acid synthesis through the non-oxidative pentose phosphate pathway[12]. Fructose promotes colon cancer metastasis toward the liver via the ketohexokinase–aldolase B pathway[11]. Little is known about the molecular mechanism underlying fructose-induced metastasis in breast cancer. We tested the possibility that KHK-A mediates breast-cancer metastasis in response to fructose. LRRC59, in concert with KPNB1, transported KHK-A to the nucleus, where KHK-A phosphorylated YWHAH at Ser[25]. This work provides the molecular mechanism underlying fructose-induced cancer metastasis
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