Increased glutamine metabolism is a hallmark of cancer. Mitochondrial glutamic pyruvate transaminase (GPT2) catalyzes the reversible transamination between alanine and α-ketoglutarate (α-KG), also known as 2-oxoglutarate, to generate pyruvate and glutamate during cellular glutamine catabolism. However, the precise role of GPT2 in tumorigenesis remains elusive. Here, we report that in breast cancer tissue samples and breast cancer cell lines, GPT2 expression level was markedly elevated and correlated with the pathological grades of breast cancers. GPT2 overexpression increased the subpopulation of breast cancer stem cells in vitro and promoted tumorigenesis in mice. GPT2 reduced α-KG level in cells leading to the inhibition of proline hydroxylase 2 (PHD2) activity involved in the regulation of HIF1α stability. Accumulation of HIF1α, resulting from GPT2-α-KG-PHD2 axial, constitutively activates sonic hedgehog (Shh) signaling pathway. Overall, GPT2 promotes tumorigenesis and stemness of breast cancer cells by activating the Shh signaling, suggesting that GTP2 is a potential target for breast cancer therapy.

中文翻译：

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谷氨酸丙酮酸转氨酶GPT2通过激活声波刺猬信号促进乳腺癌细胞的肿瘤发生。

谷氨酰胺代谢增加是癌症的标志。线粒体谷氨酸丙酮酸转氨酶（GPT2）催化丙氨酸和α-酮戊二酸（α-KG）之间的可逆转氨作用，也称为2-氧代戊二酸，在细胞谷氨酰胺分解代谢过程中产生丙酮酸和谷氨酸。但是，GPT2在肿瘤发生中的确切作用仍然难以捉摸。在这里，我们报告在乳腺癌组织样品和乳腺癌细胞系中，GPT2表达水平显着升高，并且与乳腺癌的病理学等级相关。GPT2过表达增加了体外乳腺癌干细胞的亚群并促进了小鼠的肿瘤发生。GPT2降低了细胞中的α-KG水平，从而导致脯氨酸羟化酶2（PHD2）活性的抑制与HIF1α稳定性的调节有关。由GPT2-α-KG-PHD2轴向产生的HIF1α累积组成性地激活了声刺猬（Shh）信号通路。总体而言，GPT2通过激活Shh信号传导来促进乳腺癌细胞的肿瘤发生和干细胞生长，这表明GTP2是乳腺癌治疗的潜在靶标。