Metabolic shifts toward glutamine regulate tumor growth, invasion and bioenergetics in ovarian cancer

Molecular Systems Biology

Lifeng Yang⁴  Tyler Moss⁶  Lingegowda S Mangala⁷  Juan Marini¹  Hongyun Zhao⁴  Stephen Wahlig⁴  Guillermo Armaiz-Pena⁷  Dahai Jiang⁷  Abhinav Achreja⁴  Julia Win⁴  Rajesha Roopaimoole⁷  Cristian Rodriguez-Aguayo⁵  Imelda Mercado-Uribe²  Gabriel Lopez-Berestein⁵  Jinsong Liu²  Takashi Tsukamoto³  Anil K. Sood⁷  Prahlad T Ram⁶ 

[1] Baylor College of Medicine, Houston, TX, USA;Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA;Johns Hopkins University, Baltimore, MD, USA;Laboratory for Systems Biology of Human Diseases, Rice University, Houston, TX, USA;Center for RNA Interference and Non-Coding RNA, University of Texas MD Anderson Cancer Center, Houston, TX, USA;Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA;Departments of Gynecological Oncology and Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

关键词: cancer metabolism;    glutamine dependence;    glutaminolysis;    invasion;    ovarian cancer;   

DOI  :  10.1002/msb.20134892

来源: Wiley

【 摘 要 】

Abstract

Glutamine can play a critical role in cellular growth in multiple cancers. Glutamine-addicted cancer cells are dependent on glutamine for viability, and their metabolism is reprogrammed for glutamine utilization through the tricarboxylic acid (TCA) cycle. Here, we have uncovered a missing link between cancer invasiveness and glutamine dependence. Using isotope tracer and bioenergetic analysis, we found that low-invasive ovarian cancer (OVCA) cells are glutamine independent, whereas high-invasive OVCA cells are markedly glutamine dependent. Consistent with our findings, OVCA patients’ microarray data suggest that glutaminolysis correlates with poor survival. Notably, the ratio of gene expression associated with glutamine anabolism versus catabolism has emerged as a novel biomarker for patient prognosis. Significantly, we found that glutamine regulates the activation of STAT3, a mediator of signaling pathways which regulates cancer hallmarks in invasive OVCA cells. Our findings suggest that a combined approach of targeting high-invasive OVCA cells by blocking glutamine's entry into the TCA cycle, along with targeting low-invasive OVCA cells by inhibiting glutamine synthesis and STAT3 may lead to potential therapeutic approaches for treating OVCAs.

Synopsis

Glutamine plays an important role in cellular growth in several cancers. In this study, a further link between glutamine dependency and tumor invasiveness is established in ovarian cancer. Glutamine maintains the high-invasive phenotype by regulating STAT3 signaling.

• High-invasive ovarian cancer (OVCA) cells are glutamine dependent in contrast to low-invasive cells that are glutamine independent.
• Glutamine regulates STAT3 activation in high-invasive cancer cells.
• Glutamine's entry into TCA cycle modulates the invasive potential of high-invasive cancer cells.
• The ratio of glutamine catabolism over glutamine anabolism is associated with worse overall survival in OVCA patients.

【 授权许可】

CC BY   
© 2014 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.