C-Src Promotes Tumor Cell Proliferation By Activating ACSS2

In addition to the need for energy,tumor cells depend on active syntheses of nucleic acids,proteins and fatty acids for rapid proliferation.In general,acetyl-CoA,the precursor required for the synthesis of fatty acids,is mainly derived from glycolysis.Glucose can be converted to pyruvate through glycolysis in cytosol and further to citrate via TCA cycle in mitochondria.Then citrate is transported into cytosol and cleaved to acetyl-CoA for fatty acids synthesis.Recent,researches indicate that pyruvate can be oxidized to acetate either by reactive oxygen species(ROS),or by a-keto acid dehydrogenases in the reactions of dehydrogenation,and acetate is further converted to acetyl-CoA by acetyl-CoA synthetase(ACS).This pathway has been considered playing an important role in fatty acids synthesis because it can synthesize acetyl-CoA not only from endogenous acetate,but also from exogenous acetate.Previous,study of our lab shows that c-Src can promote tumor cell proliferation by activating the rate-limitimg enzyme activity in glycolysis and thus enhancing glycolysis and the non-oxidation phase of the pentose phosphate(PP)pathway.However,it is still unknown if c-Src is involved in the regulation of fatty acids synthesis.In this thesis,we mainly explored the regulatory effect of c-Src on fatty acids de novo synthesis and the contribution of such effect on tumor cells proliferation.First,we found that c-Src can interact with acetyl-CoA synthetase 2(ACSS2)and co-localize with it.Moreover,c-Src can phosphorylate ACSS2 and consequently stimulate its enzyme activity.To investigate whether c-Src regulates fatty acids synthesis,we cultured tumor cell with isotopic labelled glucose(U13C-glucose)and acetate(1,2-13C-acetate)and detected the content of 13C labelled fatty acids.Our results demonstrate that c-Src promotes the de novo synthesis of fatty acids from acetate rather from glucose.Consistently,knocking out of ACSS2 significantly attenuates the promotion of c-Src on acetate-based fatty acid synthesis.At last,cell proliferation assays(growth curves and MTT)demonstrate that c-Src enhanced cell proliferation is partially due to its promotion of fatty acids de novo synthesis by activating ACSS2.In summary,our study reveals a novel mechanism by which c-Src promotes cell proliferation.According to this finding,disruption of the interaction between c-Src and ACSS2 may be a novel strategy for the treatment of tumors with high expression of c-Src and ACSS2.