title: Macrophages induce resistance to 5-fluorouracil chemotherapy in colorectal cancer through the release of putrescine.
abstract: The development of chemoresistance to 5-fluorouracil (5-FU) is a major obstacle for sustained effective treatment of colorectal cancer (CRC), with the mechanisms being not fully understood. Here we demonstrated that tumor associated macrophages (TAMs) became activated during treatment with 5-FU and secreted factors that protected the CRC cells against chemotherapy with 5-FU. By performing metabolomics analysis, we identified putrescine, a member of polyamines, inducing resistance to 5-FU-triggered CRC apoptosis and tumor suppression via JNK-caspase-3 pathway. Noteworthily, either pharmacological or genetic blockage of ornithine decarboxylase (ODC) prevented TAMs-induced chemoresistance to 5-FU in vitro and in vivo. Our findings show that TAMs are potent mediators of resistance to 5-FU chemotherapy and uncover potential targets to enhance chemotherapy sensitivity in patients with CRC.
authors: Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors: Xuan
authors: X
authors: Zhang
authors: Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors: Yujuan
authors: Y
authors: Chen
authors: Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors: Lijun
authors: L
authors: Hao
authors: Department of Biochemistry and Molecular Biology, Third Military Medical University, Chongqing 400038, China.
authors: Along
authors: A
authors: Hou
authors: Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors: Xiaozhen
authors: X
authors: Chen
authors: Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors: Yifei
authors: Y
authors: Li
authors: Department of Biochemistry and Molecular Biology, Third Military Medical University, Chongqing 400038, China.
authors: Rui
authors: R
authors: Wang
authors: 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, Chongqing 400038, China.
authors: Peng
authors: P
authors: Luo
authors: Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors: Zhihua
authors: Z
authors: Ruan
authors: Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors: Juanjuan
authors: J
authors: Ou
authors: 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, Chongqing 400038, China.
authors: Chunmeng
authors: C
authors: Shi
authors: Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China; Department of Biochemistry and Molecular Biology, Third Military Medical University, Chongqing 400038, China. Electronic address: hongmingmiao@sina.com.
authors: Hongming
authors: H
authors: Miao
authors: Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China. Electronic address: lianghoujie@sina.com.
authors: Houjie
authors: H
authors: Liang
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology*; D045325:HCT116 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D055432:Metabolomics / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D009955:Ornithine Decarboxylase / Q000235:genetics / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors / Q000494:pharmacology; D011700:Putrescine / Q000378:metabolism*; D000067996:RAW 264.7 Cells; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden
chemical_list: D000964:Antimetabolites, Antineoplastic; D065108:Ornithine Decarboxylase Inhibitors; D048031:JNK Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D009955:Ornithine Decarboxylase; D005472:Fluorouracil; D011700:Putrescine
keywords: Apoptosis; Chemoresistance; Colorectal cancer; Macrophage; Putrescine