Theranostics 2017; 7(12):3021-3033. doi:10.7150/thno.18992

Research Paper

Glutamic Pyruvate Transaminase GPT2 Promotes Tumorigenesis of Breast Cancer Cells by Activating Sonic Hedgehog Signaling

Yuan Cao1*, Shu-Hai Lin1*, Yongbin Wang1, Y. Eugene Chin2, Lan Kang3, Jun Mi1✉

1. Department of Biochemistry and Molecular Cell Biology; Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine;
2. Shanghai Institute for Biological Science, Chinese Academy of Sciences;
3. Institute of Cancer Stem Cell, Dalian Medical University.
* These authors contributed equally to this work.

Abstract

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.

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How to cite this article:
Cao Y, Lin SH, Wang Y, Chin YE, Kang L, Mi J. Glutamic Pyruvate Transaminase GPT2 Promotes Tumorigenesis of Breast Cancer Cells by Activating Sonic Hedgehog Signaling. Theranostics 2017; 7(12):3021-3033. doi:10.7150/thno.18992. Available from http://www.thno.org/v07p3021.htm