Lactate promotes PGE2 synthesis and gluconeogenesis in monocytes to benefit the growth of inflammation-associated colorectal tumor.
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.
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, The People's Republic of China.
Libin
L
Wei
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, The People's Republic of China.
Yuxin
Y
Zhou
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, The People's Republic of China.
Jing
J
Yao
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, The People's Republic of China.
Chen
C
Qiao
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, The People's Republic of China.
Ting
T
Ni
Xi'an Middle School of Shanxi Province, Xi'an, The People's Republic of China.
Ruichen
R
Guo
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, The People's Republic of China.
Qinglong
Q
Guo
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, The People's Republic of China.
Na
N
Lu
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003092:Colitis / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D015232:Dinoprostone / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005943:Gluconeogenesis / Q000187:drug effects*; D006019:Glycolysis / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019344:Lactic Acid / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000187:drug effects; D014945:Wound Healing; D023041:Xenograft Model Antitumor Assays
D012333:RNA, Messenger; D019344:Lactic Acid; D015232:Dinoprostone
HIF-1α; gluconeogenesis; inflammation; lactate; microenvironment