KHK-A promotes fructose-dependent colorectal cancer liver metastasis by facilitating the phosphorylation and translocation of PKM2.
Study Goal
The researchers aimed to determine fructose's role and mechanism in colorectal cancer liver metastasis (CRLM).
Results Summary
The study found that fructose absorbed by primary colorectal cancer accelerates CRLM, with KHK-A promoting metastasis via PKM2 phosphorylation, activating EMT and aerobic glycolysis. TEPP-46 treatment inhibited this pro-metastatic effect.
Population
Colorectal cancer (CRC) and colorectal cancer liver metastasis (CRLM) models (in vitro and in vivo).
Effective Dosage
Not specified
Duration
Not specified
Interactions
None mentioned
| Intervention | Direction | Endpoint | Population | Dosage | Impact | Claim # |
|---|---|---|---|---|---|---|
Excessive fructose diet | increase | colorectal cancer (CRC) progression | - | - | is closely associated with | #1 |
fructose absorbed by primary colorectal cancer | increase | colorectal cancer liver metastasis (CRLM) | - | - | could accelerate | #2 |
- | increase | expression of KHK-A in liver metastasis | - | - | was higher | #3 |
KHK-A | increase | fructose-dependent CRLM | - | - | facilitated | #4 |
KHK-A | decrease | PKM2 tetramer formation | - | - | inhibited | #5 |
KHK-A | decrease | PKM2 pyruvic acid kinase activity | - | - | inhibited | #6 |
KHK-A | increase | nuclear accumulation of PKM2 | - | - | promoted | #7 |
EMT and aerobic glycolysis activated by nuclear PKM2 | increase | CRC cells' migration ability | CRC cells | - | enhance | #8 |
EMT and aerobic glycolysis activated by nuclear PKM2 | increase | anoikis resistance | CRC cells | - | enhance | #9 |
TEPP-46 treatment | decrease | pro-metastatic effect of KHK-A | - | - | inhibited | #10 |
c-myc activated by nuclear PKM2 | increase | alternative splicing of KHK-A | - | - | promotes | #11 |
Excessive fructose diet is closely associated with colorectal cancer (CRC) progression. Nevertheless, fructose's specific function and precise mechanism in colorectal cancer liver metastasis (CRLM) is rarely known. Here, this study reported that the fructose absorbed by primary colorectal cancer could accelerate CRLM, and the expression of KHK-A, not KHK-C, in liver metastasis was higher than in paired primary tumors. Furthermore, KHK-A facilitated fructose-dependent CRLM in vitro and in vivo by phosphorylating PKM2 at Ser37. PKM2 phosphorylated by KHK-A inhibited its tetramer formation and pyruvic acid kinase activity but promoted the nuclear accumulation of PKM2. EMT and aerobic glycolysis activated by nuclear PKM2 enhance CRC cells' migration ability and anoikis resistance during CRLM progression. TEPP-46 treatment, targeting the phosphorylation of PKM2, inhibited the pro-metastatic effect of KHK-A. Besides, c-myc activated by nuclear PKM2 promotes alternative splicing of KHK-A, forming a positive feedback loop.