The Study On Inhibition Of The Oncogene-induced Senescence In Premalignant Cells By Lactate Through Smad/Snail Signaling Pathway

Background and objective: Aerobic glycolysis is not only a prominent characteristic of tumor cells,but also an early event of tumor,which leads to high accumulation of lactate in tumor microenvironment.Clinical evidence has linked elevated lactate concentration with poor prognosis.However,the role and molecular mechanisms of lactate in cellular senescence and tumor progression remain elusive.Materials and methods:The function of Snail in lactate-induced EMT in lung cancer cells was explored by wound healing assay and cell invasion assay.The q RTPCR and dual luciferase reporter assay were performed to investigate how lactate regulates Snail expression.The level of TGF-?1 in culture supernatant of cells was measured by ELISA for its correlation with extracellular levels of lactate.Ras activity assay and SA-?-gal activity assay were established to determine the effect of lactate on oncogene-induced senescence in human lung epithelial cells.Ch IP assays were conducted to determine the binding of snail to p16INK4 a promoter.Two TCGA data sets(TCGA-LUAD and TCGA-LUSC)were used to explore the correlations between SNAI1 and CDKN2 A expression.Results:In this study,we showed the invasive and migratory potential of lung cancer cells was significantly enhanced by lactate and was directly linked to snail activity.We also demonstrated that extracellular acidification itself is a direct cause of the increased snail expression and physiologically coupled to LDHA dependent conversion of pyruvate to lactate.Mechanistically,lactate exerts its central function in induction of snail and EMT by directly remodeling ECM and releasing activated TGF-?1.We also demonstrated that Snail help premalignant cells to escape the oncogene-induced senescence by directly targeting and inhibiting p16INK4 a expression.Conclusions:Our study extends the understanding of EMT in tumorigenesis by uncovering the role of snail in cellular senescence.This study also reveals lactate may be a potent tumor-promoting factor and provides the basis for the development of lactate-targeted therapy.