Oncotarget

Research Papers:

Lactate promotes PGE2 synthesis and gluconeogenesis in monocytes to benefit the growth of inflammation-associated colorectal tumor

Libin Wei, Yuxin Zhou, Jing Yao, Chen Qiao, Ting Ni, Ruichen Guo, Qinglong Guo and Na Lu _

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Oncotarget. 2015; 6:16198-16214. https://doi.org/10.18632/oncotarget.3838

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Abstract

Libin Wei1, Yuxin Zhou1, Jing Yao1, Chen Qiao1, Ting Ni1, Ruichen Guo2, Qinglong Guo1 and Na Lu1

1 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, The People’s Republic of China

2 Xi′an Middle School of Shanxi Province, Xi′an, The People’s Republic of China

Correspondence to:

Qinglong Guo, email:

Na Lu, email:

Keywords: lactate, HIF-1α, gluconeogenesis, inflammation, microenvironment

Received: October 25, 2014 Accepted: March 20, 2015 Published: April 15, 2015

Abstract

Reprogramming energy metabolism, such as enhanced glycolysis, is an Achilles’ heel in cancer treatment. Most studies have been performed on isolated cancer cells. Here, we studied the energy-transfer mechanism in inflammatory tumor microenvironment. We found that human THP-1 monocytes took up lactate secreted from tumor cells through monocarboxylate transporter 1. In THP-1 monocytes, the oxidation product of lactate, pyruvate competed with the substrate of proline hydroxylase and inhibited its activity, resulting in the stabilization of HIF-1α under normoxia. Mechanistically, activated hypoxia-inducible factor 1-α in THP-1 monocytes promoted the transcriptions of prostaglandin-endoperoxide synthase 2 and phosphoenolpyruvate carboxykinase, which were the key enzyme of prostaglandin E2 synthesis and gluconeogenesis, respectively, and promote the growth of human colon cancer HCT116 cells. Interestingly, lactate could not accelerate the growth of colon cancer directly in vivo. Instead, the human monocytic cells affected by lactate would play critical roles to ‘feed’ the colon cancer cells. Thus, recycling of lactate for glucose regeneration was reported in cancer metabolism. The anabolic metabolism of monocytes in inflammatory tumor microenvironment may be a critical event during tumor development, allowing accelerated tumor growth.


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