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Cancer Res. 2018 Apr 15;78(8):1972-1985. doi: 10.1158/0008-5472.CAN-17-3155.

ME1 Regulates NADPH Homeostasis to Promote Gastric Cancer Growth and Metastasis.

Lu YX#1,2, Ju HQ#1, Liu ZX#1, Chen DL1,2, Wang Y1,2, Zhao Q1, Wu QN1,2, Zeng ZL1, Qiu HB1,3, Hu PS1, Wang ZQ1,2, Zhang DS1,2, Wang F4,2, Xu RH4,2.

Author information

1
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
2
Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.
3
Department of Gastric and Pancreatic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China.
4
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. xurh@sysucc.org.cn wangfeng@sysucc.org.cn.
#
Contributed equally

Abstract

Genomic alterations of tumor suppressorsoften encompass collateral protein-coding genes that create therapeutic vulnerability to further inhibition of their paralogs. Here, we report that malic enzyme 2 (ME2) is frequently hemizygously codeleted with SMAD4 in gastric cancer. Its isoenzyme ME1 was upregulated to replenish the intracellular reducing equivalent NADPH and to maintain redox homeostasis. Knockdown of ME1 significantly depleted NADPH, induced high levels of reactive oxygen species (ROS), and ultimately cell apoptosis under oxidative stress conditions, such as glucose starvation and anoikis, in ME2-underexpressed cells. Moreover, ME1 promoted tumor growth, lung metastasis, and peritoneal dissemination of gastric cancer in vivo Intratumoral injection of ME1 siRNA significantly suppressed tumor growth in cell lines and patient-derived xenograft-based models. Mechanistically, ME1 was transcriptionally upregulated by ROS in an ETV4-dependent manner. Overexpression of ME1 was associated with shorter overall and disease-free survival in gastric cancer. Altogether, our results shed light on crucial roles of ME1-mediated production of NADPH in gastric cancer growth and metastasis.Significance: These findings reveal the role of malic enzyme in growth and metastasis.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/8/1972/F1.large.jpg Cancer Res; 78(8); 1972-85. ©2018 AACR.

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