Macrophage ABHD5 promotes colorectal cancer growth by suppressing spermidine production by SRM

Hongming Miao, Juanjuan Ou, Yuan Peng, Xuan Zhang, Yujuan Chen, Lijun Hao, Ganfeng Xie, Zhe Wang, Xueli Pang, Zhihua Ruan, Jianjun Li, Liqing Yu, Bingzhong Xue, Hang Shi, Chunmeng Shi () and Houjie Liang ()
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Hongming Miao: Southwest Hospital, The Third Military Medical University
Juanjuan Ou: Southwest Hospital, The Third Military Medical University
Yuan Peng: Southwest Hospital, The Third Military Medical University
Xuan Zhang: Southwest Hospital, The Third Military Medical University
Yujuan Chen: Southwest Hospital, The Third Military Medical University
Lijun Hao: Southwest Hospital, The Third Military Medical University
Ganfeng Xie: Southwest Hospital, The Third Military Medical University
Zhe Wang: Southwest Hospital, The Third Military Medical University
Xueli Pang: Southwest Hospital, The Third Military Medical University
Zhihua Ruan: Southwest Hospital, The Third Military Medical University
Jianjun Li: Southwest Hospital, The Third Military Medical University
Liqing Yu: University of Maryland
Bingzhong Xue: Georgia State University
Hang Shi: Georgia State University
Chunmeng Shi: Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University
Houjie Liang: Southwest Hospital, The Third Military Medical University

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: Abstract Metabolic reprogramming in stromal cells plays an essential role in regulating tumour growth. The metabolic activities of tumour-associated macrophages (TAMs) in colorectal cancer (CRC) are incompletely characterized. Here, we identify TAM-derived factors and their roles in the development of CRC. We demonstrate that ABHD5, a lipolytic co-activator, is ectopically expressed in CRC-associated macrophages. We demonstrate in vitro and in mouse models that macrophage ABHD5 potentiates growth of CRC cells. Mechanistically, ABHD5 suppresses spermidine synthase (SRM)-dependent spermidine production in macrophages by inhibiting the reactive oxygen species-dependent expression of C/EBPɛ, which activates transcription of the srm gene. Notably, macrophage-specific ABHD5 transgene-induced CRC growth in mice can be prevented by an additional SRM transgene in macrophages. Altogether, our results show that the lipolytic factor ABHD5 suppresses SRM-dependent spermidine production in TAMs and potentiates the growth of CRC. The ABHD5/SRM/spermidine axis in TAMs might represent a potential target for therapy.

Date: 2016
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DOI: 10.1038/ncomms11716

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