Endoplasmic Reticulum Stress Promotes Gastric Cancer Cell Invasion And Migration Via PI3K/AKT Pathway

Background and ObjectiveVarious stress factors such as lack of the oxygen and nutrient deprivation,protein glycolysation dysfunction and calcium metabolism disorder can lead to the obstacle of the protein folding.Unfolded protein accumulation in the endoplasmic reticulum lumen resμlts in the endoplasmic reticulum stress,which activates a series of self protective responses,called the unfolded protein response.Tumor metastasis is associated with many pathways,Many studies have shown that,PI3K/AKT pathway can promote tumor cell invasion and migration.PI3K/AKT pathway is one of the important signal transduction pathways,which is greatly activated in the metastatic of tumor cells.PI3K activate metalloproteinases MMP-2,MMP-9,leading to the degradation of extracellular matrix(ECM).It also promotes tumor cell invasion and metastasis by reduce the expression of E-cadherin.In the early gastric cancer and middle-late gastric cancer,PI3K protein expression positive cell rate are dramaticaly higher than that in normal gastric mucosa tissues.Our previous data showed that ER stress promotes gastric cancer cell migration and invasion.Howvere,the role of PI3K/AKT pathway in the endoplasmic reticulum stress-induced gastric cancer cell invasion and migration remains elusive.Here,gastric cancer cell lines BGC823 and SGC7901 were used to study the role of PI3K/AKT pathway in the endoplasmic reticulum stress-induced invasion and migration in gastric cancer cells.Materials and methods1.Whole cell lysates of BGC823 and SGC7901 gastric cancer cells were collected after the treatment of the ER stress inducer tunicamycin or thapsigargin for different periods.The phosphorylation levels of AKT were detected.2.Whole cell lysates of BGC823 and SGC7901 gastric cancer cells were collected after the treatment of ERS inducer with or without the PI3K inhibitor wortmannin or Ly294002.The phosphorylation levels of AKT were detected.3.BGC823 and SGC7901 gastric cancer cells were treated by ER stress inducer with or without the PI3K inhibitor wortmannin(1uM)or Ly294002(25uM).Wound healing assay and transwell assay were used to examine the changes of the cell migration and invasion abilities.Western blot was emoloyed to study the expression changes of the metastasis-related proteins E-cadherin、N-cadherin、MMPs and VEGF.Resμlts:1.Endoplasmic reticulum stress active PI3K/Akt pathway Compared with that in the control group,AKT phosphorylation leves were increased significantly in tunicamycin or thapsigargin-treated BGC823 and SGC7901 gastric cancer cells(P < 0.05).2.PI3K inhibitors inhibit PI3K/Akt pathway in Endoplasmic reticulum stress response Compared with that without the PI3K inhibitor,AKT phosphorylation leves were decreased significantly in BGC823 and SGC7901 gastric cancer cells treated with the ER stess inducer plus the PI3K inhibitor Wortmannin(1uM)and Ly294002(25uM)(P < 0.05).3.Endoplasmic reticulum stress promotes gastric cancer cell invasion and migration via PI3K/AKT pathway Compared with that without PI3K inhibitor,wound healing and transewell assay showed that the abilities of cell migration and invasion were decreased significantly in BGC823 and SGC7901 gastric cancer cells treated with the ER stess inducer plus the PI3K inhibitor.Western blot showed that the expressions of the metastasis-associated proteins E –cadherin,N-cadherin,MMP-2 and MMP-9 and VEGF were dramatically higher in BGC823 and SGC7901 gastric cancer cells treated with the ER stess inducer plus the PI3K inhibitor than that without it(P < 0.05).Conclusions :Endoplasmic reticulum stress activate the PI3K/Akt pathway,promote the gastric cancer cell invasion and migration via induce gastric cells Epithelial to Mesenchymal Transition and Promote the expressions of the metastasis-associated proteins MMP-2 and MMP-9 and VEGF.