Insulin inhibits Abeta production through modulation of APP processing in a cellular model of Alzheimer's disease.

OBJECTIVE: Amyloid-beta (Abeta) is a 36-43 amino acid peptide that is derived by processing of the beta-amyloid precursor protein (APP). Abeta plays a central role in the development of Alzheimer's disease (AD). Although growing evidence suggests that insulin has important functions in Abeta metabolism, the underlying mechanisms are still unknown. METHODS: Using an SH-SY5Y cell line overexpressing human APP Swedish mutant (APPsw), we evaluated the effect of insulin on APP processing and Abeta production by using western blot analysist. RESULTS: Our data showed that administration of insulin reduced the Abeta generation in culture media with a concomitant decreases in the levels of beta-secretase BACE1, secreted extracellular domain (sAPPbeta) and a fragment of 99 amino acids (C99) in APPsw cells. We further showed that insulin increased the levels of alpha-secretase ADAM10, a secreted extracellular domain secreted (sAPPa) and a fragment of 83 amino acids (C83) in APPsw cells. CONCLUSION: Our present data suggest that insulin could inhibit Abeta production through modulation of APP processing by increasing cleavage at the a-secretase site and decreased cleavage at the beta-secretase sites.

Targeting EGFR sensitizes 5-Fu-resistant colon cancer cells through modification of the lncRNA-FGD5-AS1-miR-330-3p-Hexokinase 2 axis.

5-Fluorouracil (5-Fu) is a widely applied anti-cancer agent against colorectal cancer (CRC), yet a number of CRC patients have developed resistance to 5-Fu-based chemotherapy. The epidermal growth factor receptor (EGFR) is recognized as an oncogene that promotes diverse cancer progresses. In addition, long noncoding RNAs (lncRNAs) are essential regulators of cancers. Here we report that EGFR and lncRNA-FGD5-AS1 promoted 5-Fu resistance of CRC. By establishing the 5-Fu-resistant CRC cell line, we detected that EGFR, FGD5-AS1, and glucose metabolism were significantly elevated in 5-Fu-resistant CRC cells. A microRNA-microarray analysis revealed that miR-330-3p functions as a downstream effector of FGD5-AS1. FGD5-AS1 directly sponged miR-330-3p to form a competing endogenous RNA (ceRNA) network, leading to inhibition of miR-330-3p expression. Furthermore, bioinformatics analysis revealed that Hexokinase 2 (HK2) was a potential target of miR-330-3p, which was validated by luciferase assay. Rescue experiments demonstrated that FGD5-AS1 promotes glycolysis through modulating the miR-330-3p-HK2 axis, leading to 5-Fu resistance of CRC cancer cells. Finally, in vitro and in vivo xenograft experiments consistently demonstrated that inhibition of EGFR by the specific inhibitor erlotinib effectively enhanced the anti-tumor toxicity of 5-Fu by targeting the EGFR-FGD5-AS1-miR-330-3p-HK2 pathway. In summary, this study demonstrates new mechanisms of the EGFR-modulated 5-Fu resistance through modulating the noncoding RNA network, contributing to development of new approaches against chemoresistant CRC.