BABAM1:A Key Regulator For Serine Synthesis Pathway Via PHDGH In Breast Cancer Cell Lines

Cancer has become the most serious threat towards human health over the past decades.With the industrialization of morden society,genetic factors interact with environmental factors,including those brought about by changes in living styles,playing roles as the major contributor to the pathogenesis of cancer.Considering breast cancer is the most common type of cancer among women,inverstigation of the intrinsic signaling pathways among breast cancer cells using ecotoxicology tools such as LC-MS will be of great significance.Recent discoveries have revealed that serine synthesis pathway can provide the cancer cells with extra energy and building blocks of biomacromolecules,making serine metabolism a hot spot in cancer research fileds.The BABAM1 gene was found as a member of BRCA1-A DNA damage repair complex,but its function in cell metabolism remains unexplored.In our study,PHGDH,a rate-limiting enzyme catalyzing the first step of serine biosynthesis,is identified as an interacting protein of BABAM1 by immunoprecipitation and proteomic analysis.The interaction between PHGDH with the VWFA domain of BABAM1 was enhanced with the absence of glucose,elevating the catalytic activity PHGDH.In addition,evidence has shown that the interaction between PHGDH and BABAM1 might be inhibited by the phosphorylation through PKC?.Moreover,by using Q-ExactiveTM Hybrid Quadrupole Orbitrap LC-MS,we were able to trace the metabolites within the breast cancer cells with stable isotopes.Loss of BABAM1 reduced flux to TCA cycle from L-glutamine due to impaired function of PHGDH.Damaged cellular redox homeostasis indicated by significantly reduced GSH/GSSG ratio was found in cells deficient of BABAM1,rendering these cells vulnerable to glucose deprivation.All these findings suggest that BABAM1 is critical in serine synthesis pathway,providing new avenue for better understanding of cancer metabolism and development of drugs to treat breast cancer.