Abstract 5143: ErbB2 activation up-regulates glutaminase 1 expression via NF-κB pathway

Abstract

Active glutamine utilization is essential for cell proliferation in many tumors, for it provides critical carbon and nitrogen sources. Glutaminolysis represents the first and rate-limiting step of glutamine utilization and is catalyzed by glutaminase. Previous studies have shown that c-Myc regulates glutaminolysis by increasing glutaminase expression in tumor cells. However, it remains unclear whether other oncogenic signaling pathways promote glutaminolysis. Breast cancer is the second most common cause of death for women in the United States and ErbB2 activation is one of the major causes of breast cancer. Using MCF10A and MCF10A-derived NeuT cells, we studied the effect of ErbB2 activation on glutaminase expression, and found that ErbB2 activation increased glutaminase 1 expression at both mRNA and protein levels. Knockdown of ErbB2 decreased glutaminase 1 expression in several human ErbB2-positive cell lines. Consistently, blocking ErbB2 signaling pathway by trastuzumab repressed glutaminase 1 expression. We further showed that in these cells, ErbB2-mediated up-regulation of glutaminase 1 was independent of c-Myc expression. In addition, we found that activation of PI3K/Akt or MAPK pathway was not sufficient to up-regulate glutaminase 1 expression. Instead, inhibition of NF-κB down-regulated glutaminase 1 expression whereas stimulation of NF-κB induced glutaminase 1 expression, suggesting a PI3K/Akt-independent activation of NF-κB signaling pathway up-regulates glutaminase 1. Finally, inhibition of glutaminase activity significantly decreased human breast cancer cell proliferation. Our data indicate that ErbB2 activation promotes glutaminase 1 expression via NF-κB in breast cancer cells, identifying another oncogenic signaling pathway which stimulates glutamine utilization. These findings may facilitate the identification of novel targets for cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5143. doi:1538-7445.AM2012-5143

Design and evaluation of novel glutaminase inhibitors

“…7,8,9 GAC upregulation is present in multiple cancer cell lines, correlates with increased proliferative rates, and it is linked to the dysregulation of a number of pathways, including the dysregulation/amplification of the Myc oncogene. 10,11,12,13 …”