BRCA1/GOT2调控代谢重编程影响乳腺癌对甲氨蝶呤敏感性的研究

Metabolic reprogramming is one of the hallmarks of cancer. Recent researches have revealed a potential role of breast and ovarian cancer susceptibility gene 1 (BRCA1) in abnormal cancer cell metabolism. However, the underlying mechanism of how BRCA1 mediates metabolic reprogramming remains unclear. Our results show that BRCA1 transcriptionally regulates the expression of GOT2 and further modulates aspartate synthesis. Moreover, we find GOT2 over-expression can increase the sensitivity of methotrexate (MTX) in breast cancer cells. It has been reported that triple negative breast cancers (TNBCs) have better responses to CMF, a MTX containing chemotherapy regimen, than other breast cancer subtypes. Approximately 15-30% of TNBCs have BRCA1 deficiency. Based on these observations, we assume that the better efficacy of CMF in TNBC may be associated with the BRCA1/GOT2 mediated abnormal aspartate synthesis. This research investigates this assumption and elucidates the mechanism of how BRCA1 regulates GOT2 and modulates abnormal cell metabolism.

代谢重编程是肿瘤细胞的重要特征之一。近年来的研究提示乳腺癌易感基因1(BRCA1)可能参与肿瘤细胞代谢调控，然而，尚不清楚其具体途径。我们前期发现，BRCA1 可能在转录层面上调控谷草转氨酶 2(GOT2)。GOT2能够催化生成天冬氨酸。天冬氨酸是生物体内多种氨基酸及嘌呤、嘧啶碱基的合成前体，是肿瘤细胞增殖过程中重要的代谢中间产物。我们发现在 BRCA1 表达降低的细胞中，GOT2 表达上调，天冬氨酸合成增加，促进了细胞增殖。此外，过表达GOT2能导致乳腺癌细胞对甲氨蝶呤(MTX)敏感性增强。近年来临床研究结果显示含MTX的CMF化疗方案在三阴性乳腺癌中疗效更好，而三阴性乳腺癌常有BRCA1异常。根据这些现象，我们推测BRCA1可能通过调控GOT2影响乳腺癌细胞天冬氨酸的合成，从而影响恶性增殖和对MTX敏感性。本研究拟证实上述假设，并对BRCA1调控GOT2影响代谢的机制进行深入阐述。

代谢重编程是肿瘤细胞的重要特征之一。近年来的研究提示乳腺癌易感基因1(BRCA1)可能参与肿瘤细胞代谢的调控，然而，尚不清楚其具体途径。我们的研究发现，BRCA1能在转录层面上调控谷草转氨酶2(GOT2)。GOT2能够催化底物产生天冬氨酸。天冬氨酸是细胞内多种氨基酸及嘌呤、嘧啶碱基的合成前体，是肿瘤细胞增殖过程中重要的代谢中间产物。BRCA1能够与转录抑制因子ZBRK1形成复合体并通过ZBRK1直接结合在GOT2的启动子区域抑制GOT2的转录。干扰BRCA1/ZBRK1复合体促进GOT2的表达，进而产生更多的天冬氨酸和α酮戊二酸，促进乳腺癌细胞增殖。通过临床组织标本研究，我们发现GOT2在乳腺癌中过表达并且可以作为独立的生存预后因素。很有趣的是，GOT2过表达能够增强乳腺癌细胞对甲氨蝶呤的敏感性。综上，本项目证实BRCA1能通过调控GOT2影响乳腺癌细胞天冬氨酸的合成，从而影响恶性增殖和对MTX敏感性。