燕麦生物碱A通过调控丝氨酸羟甲基转移酶2重塑丝氨酸代谢抑制结肠癌生长  

Avenanthramide A Attenuates Colorectal Cancer Growth via Regulating SHMT2 to Reshape Serine Metabolism

作　　者：付荣 王珏[2] 王海龙[1] 杨鹏[3] FU Rong;WANG Jue;WANG Hai-Long;YANG Peng(School of Basic Medical Sciences,Shanxi Medical University,Taiyuan 030001,China;First Hospital of Shanxi Medical University,Taiyuan 030001,China;Institute of Biotechnology,Shanxi University,Taiyuan 030006,China)

机构地区：[1]山西医科大学基础医学院,太原030001 [2]山西医科大学第一医院,太原030001 [3]山西大学生物技术研究所,太原030006

出　　处：《中国生物化学与分子生物学报》2023年第5期715-723,共9页Chinese Journal of Biochemistry and Molecular Biology

基　　金：国家自然科学基金(No.32200321,31800657,82003146);山西省自然科学基金青年项目(No.20210302124252)资助。

摘　　要：流行病学研究表明,燕麦类全谷食品可有效降低结肠癌的发病风险。丝氨酸/甘氨酸代谢途径对于维持肿瘤生长十分重要,能为肿瘤细胞核苷酸等生物大分子的合成提供底物,并保障肿瘤细胞免受氧化损伤。我们的前期研究表明,燕麦生物碱A(avenanthramide A,AVN A)具有抑制小鼠原位结肠癌生长的作用。本研究通过对氧化偶氮甲烷/葡聚糖硫酸钠(azoxymethane/dextran sulphate sulfate,AOM/DSS)小鼠结肠癌模型进行血液代谢组学研究,发现AVN A处理后,丝氨酸/甘氨酸代谢途径的变化最为显著(P<0.01)。丝氨酸、甘氨酸饥饿条件下,AVN A对结肠癌的杀伤效果显著增强(P<0.05),表明AVN A靶向丝氨酸代谢从而发挥抗结肠癌作用。随后,对丝氨酸代谢关键酶SHMT1、SHMT2、PHGDH、PSAT1及PSPH的mRNA及蛋白质表达水平进行检测,发现AVN A明显抑制SHMT2的表达(P<0.01或P<0.001)。过表达SHMT2后,由AVN A介导的对结肠癌细胞的生长、增殖、GSH/GSSG以及NADPH/NADP+的抑制作用均被逆转。综上所述,AVN A通过下调SHMT2的表达,阻遏丝氨酸/甘氨酸代谢途径,从而发挥抑制结肠癌进展的作用。本研究为燕麦生物碱的深度利用及结肠癌的营养干预提供一定的理论依据。Epidemiological studies showed that the intake of oats can effectively reduce the risk of colorectal cancer.The serine/glycine metabolic pathway plays an important role in maintaining tumor growth,providing tumor cells with the substrates required for the synthesis of biomacromolecules such as nucleotides,and protecting tumor cells from oxidative damage.Our previous results showed that avenanthramide A(AVN A),a unique alkaloid in oats,inhibits the growth of orthotopic colon cancer in mice.Here,blood metabolomic analysis was performed on the azoxymethane/dextran sodium sulfate(AOM/DSS)mouse model,and the results showed that the serine/glycine metabolic pathway changed most significantly after AVN A treatment(P<0.01).Under the condition of serine and glycine starvation,the killing effect of AVN A on colon cancer was markedly enhanced(P<0.05),indicating that AVN A targets serine metabolism to exert an anti-colon cancer effect.Subsequently,the mRNA and protein levels of key serine metabolism enzymes including SHMT1,SHMT2,PHGDH,PSAT1 and PSPH were examined,and the result showed that AVN A obviously decreased SHMT2 expression(P<0.01 or P<0.001).AVN Amediated suppression of colon cancer cell growth,proliferation,GSH/GSSG,and NADPH/NADP+were all reversed by the overexpression of SHMT2.Collectively,AVN A inhibits the progress of colon cancer by repressing the expression of SHMT2 and attenuating the serine/glycine metabolic pathway.These findings provide a theoretical basis for the further utilization of avenanthramide and nutritional intervention of colon cancer.

关 键 词：燕麦生物碱A 丝氨酸羟甲基转移酶2 丝氨酸代谢 结肠癌 

分 类 号：Q591[生物学—生物化学]