Autophagy is considered as an important switch for cell transformation from normal to malignant during colorectal cancer development. Consistent with other reports, we found the membrane receptor Neuropilin1 (NRP1) is greatly upregulated in colon cancer cells that underwent autophagy upon glucose deprivation. However, the mechanism underlying NRP1 regulation of autophagy is unknown. We found that knockdown of the NRP1 inhibits autophagy and largely upregulates the expression of Aldo-Keto Reductase family 1 B10 (AKR1B10). Moreover, we demonstrated that AKR1B10 interacts with and inhibits the nuclear import of Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and then subsequently represses autophagy. Interestingly, we also found a NADPH-dependent reduction reaction could be induced when AKR1B10 interacts with GAPDH and the reductase activity of AKR1B10 is important for its repressing autophagy. Together, our findings unravel a novel mechanism of NRP1 in regulating autophagy through AKR1B10.
Aldo-keto reductase family 1, member B10 (AKR1B10) has been reported to be involved in tumorigenesis of various cancer. In our studies, we evaluated the relationship between AKR1B10 expression and clinicopathological characteristics in colon cancer and showed that AKR1B10 expression was significantly correlated with TNM stage and clinical stage of colon cancer. It has been reported that colorectal cancer is closely associated with chronic inflammation and the underlying molecular mechanisms are still elusive. Here we found that knockdown of AKR1B10 significantly decreased the expression of the inflammatory cytokines, IL1α and IL6, induced by lipopolysaccharide (LPS) via inhibiting NF-κB signaling pathway. Furthermore, AKR1B10 depends on its reductase activity to affect the NF-κB signaling pathway and subsequently affect the production of inflammatory cytokines. In addition, knockdown of AKR1B10 effectively reduced cell proliferation and clonogenic growth, indicating the biologic role of AKR1B10 in colon cancer. Collectively, our findings provided important insights into a previously unrecognized role of AKR1B10 in colon cancer.
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