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MACC1 supports human gastric cancer growth under metabolic stress by enhancing the Warburg effect

Oncogene volume 34, pages 2700–2710 (2015)Cite this article

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Abstract

Cancer cells mainly metabolize by glycolysis (the Warburg effect) and are better adapted to resist metabolic stress. Metastasis-associated in colon cancer-1 (MACC1) is an oncogene promoting gastric cancer (GC) growth and metastasis, and its expression positively correlates with GC progression. However, it is unknown why MACC1 elevates with GC progression and what is its role in cancer metabolism. In this study, we discovered that MACC1 expression was significantly upregulated via adenosine monophosphate-activated protein kinase signaling in response to glucose deprivation-induced metabolic stress. Clinical observation demonstrates that MACC1 expression was higher in advanced stage GC. MACC1 expression was proved to be positively correlated with the maximum standardized uptake value of 18F-deoxyglucose in the patients, and MACC1 enhanced 18F-deoxyglucose uptake in GC cells and the xenografts. The underlying mechanism was that MACC1 promoted the Warburg effect by upregulating the activities and expressions of a series of glycolytic enzymes, including hexokinase, pyruvate dehydrogenase kinase and lactate dehydrogenase, in GC cells. This metabolic shift enhanced cell viability and resistance to apoptosis by facilitating ATP generation, reducing the reactive oxygen species production and stabilizing the mitochondrial membrane potential. In contrast, MACC1-silenced or the Warburg effect-blocked GC cells were more vulnerable to metabolic stress. In conclusion, metabolic stress is one of the mechanisms that elevate MACC1 expression in GC, and MACC1 upregulation compensatively ensures GC growth against metabolic stress by facilitating the Warburg effect.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (31271564 to WL), Guangzhou science and technology plan (134600108 to WL), the Team Program of Natural Science Foundation of Guangdong Province (S2011030003134 to WL and YL) and the Special Foundation for National Clinical Specialties of China (to Department of Oncology, Nanfang Hospital). We thank Professor Quanshi Wang and Professor Hubing Wu for helping clinical PET data acquisition, Dr Yanjiang Han for assistance with microPET, Professor Zhenhua Ding for assistance with γ-radiation activity monitor and Jingwen Zhang for language editing. QW, HW and YH are from PET Center, JZ is from Department of Cardiology, Nanfang Hospital and ZD is from Department of Radiation Medicine, School of Public Health and Tropical Medicine, Southern Medical University.

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  1. L Lin and H Huang: These authors contributed equally to this study.

Authors and Affiliations

  1. Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China

    L Lin, H Huang, W Liao, H Ma, J Liu, L Wang, N Huang & W Liao

  2. Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Y Liao

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  1. L Lin
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Correspondence to W Liao.

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Lin, L., Huang, H., Liao, W. et al. MACC1 supports human gastric cancer growth under metabolic stress by enhancing the Warburg effect. Oncogene 34, 2700–2710 (2015). https://doi.org/10.1038/onc.2014.204

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