Molecular Mechanism Of FOXO1 Regulating Tumor Cell Metabolism

Background:Tumor is one of the important diseases endangering human health.During the occurrence and development of tumor,cancer cells will reshape the metabolic network to maintain their rapid proliferation and viability.Therefore,metabolic reprogramming is one of the important signs of tumor deterioration.Abnormal changes in glucose metabolism and ammonia metabolism pathways within cancer cells can further interact with cellular signaling and epigenetics,promoting tumor development.More and more studies have shown that the occurrence of metabolic reprogramming in tumor cells is closely related to genes or transcription factors involved in metabolic regulation.Among them,FOXO1,a transcription factor with dual biological functions of promoting and inhibiting cancer,participates in and regulates many cells biological processes,including tumor cell proliferation,apoptosis,energy metabolism and cell stress response.In recent years,studies have found that different levels of FOXO1 expression in cancer cells not only have different regulatory effects on tumor cell growth,but also have an impact on the poor prognosis of tumor patients.However,the molecular mechanism behind this is still unclear.Objective and methods:From the perspective of tumor cell metabolism,this topic comprehensively used the experimental methods of biochemistry,cell biology,targeted metabonomic and enzyme catalysis dynamics to study the metabolic and proliferation regulation mechanism of FOXO1 on glioma and breast cancer cells.Results:1.The expression of glucose 6-phosphate dehydrogenase(G6PD),a key enzyme in the FOXO1 transcriptional activation of the pentose phosphate pathway:The chromatin immunoprecipitation experiments showed that G6PD was the target gene of FOXO1,and FOXO1 responded to the stress response of cells by activating the expression of G6PD.In addition,LC-MS experiments found that activation of G6PD expression by FOXO1 can promote the pentose phosphate pathway and mediate the production of downstream metabolite NADPH.2.FOXO1 enhances the antioxidant defense ability of tumor cells and the growth of glioma by activating the expression of G6PD:Using flow cytometry,it was found that FOXO1 activation of G6PD mediated NADPH production can reduce the apoptosis rate of tumor cells at high ROS levels and enhance the antioxidant defense ability of tumor cells.In addition,the experiments of cell proliferation and subcutaneous tumorigenesis in nude mice showed that the activation of G6PD expression by the transcription factor FOXO1 with dual biological regulation function can promote the growth of glioma cells in vivo and in vitro,but it does not mediate the proliferation of breast cancer cells.3.FOXO1 transcription inhibits the expression of urea cycle metabolizing enzyme argininosuccinate lyase(ASL)in breast cancer cells:ASL is the target gene of FOXO1,and FOXO1 can inhibit the ammonia clearance and urea production ability of breast cancer cells by inhibiting the expression of ASL,so that ammonia in breast cancer cells can accumulate.4.FOXO1 inhibits the growth ability of breast cancer cells in vivo and in vitro by regulating the expression of ASL:The chromatin immunoprecipitation experiments showed that ASL was the target gene of FOXO1.LC-MS experiment found that FOXO1 could inhibit the ammonia clearance and urea production of breast cancer cells by inhibiting the expression of ASL,so that ammonia in breast cancer cells could accumulate,thereby inhibiting the growth of breast cancer cells.Conclusion:The transcription factor FOXO1 with dual biological regulation function can regulate the growth of glioma and breast cancer cells by regulating pentose phosphate pathway and urea cycle metabolism.In glioma cells,the expression level of FOXO1 is relatively high,and the high-level expression of FOXO1 promotes the expression of the key enzyme G6PD in the pentose phosphate pathway,futher activating the pentose phosphate pathway,causing glioma cells to produce more NADPH,thereby improving the antioxidant and proliferative abilities of glioma cells.However,the expression of G6PD activated by FOXO1 does not mediate the growth of breast cancer cells,on the contrary,FOXO1 will inhibit the growth of breast cancer cells.In breast cancer cells:the expression level of FOXO1 is relatively low.The low level of FOXO1 inhibits the expression of arginine succinate lyase(ASL),a urea cycle metabolizing enzyme,through transcription,so that ammonia and urea metabolism in breast cancer cells are disordered,thus inhibiting the migration and proliferation of breast cancer cells.