title: In vivo amelioration of endogenous antitumor autoantibodies via low-dose P4N through the LTA4H/activin A/BAFF pathway.
abstract: Cancer progression is associated with the development of antitumor autoantibodies in patients' sera. Although passive treatment with antitumor antibodies has exhibited remarkable therapeutic efficacy, inhibitory effects on tumor progression by endogenous antitumor autoantibodies (EAAs) have been limited. In this study, we show that P4N, a derivative of the plant lignan nordihydroguaiaretic acid (NDGA), enhanced the production of EAAs and inhibited tumor growth at low noncytotoxic concentrations via its immunoregulatory activity. Intratumoral injection of P4N improved the quantity and quality of EAAs, and passive transfer of P4N-induced EAAs dramatically suppressed lung metastasis formation and prolonged the survival of mice inoculated with metastatic CT26 tumor cells. P4N-induced EAAs specifically recognized two surface antigens, 78-kDa glucose-regulated protein (GRP78) and F1F0 ATP synthase, on the plasma membrane of cancer cells. Additionally, P4N treatment led to B-cell proliferation, differentiation to plasma cells, and high titers of autoantibody production. By serial induction of autocrine and paracrine signals in monocytes, P4N increased B-cell proliferation and antibody production via the leukotriene A4 hydrolase (LTA4H)/activin A/B-cell activating factor (BAFF) pathway. This mechanism provides a useful platform for studying and seeking a novel immunomodulator that can be applied in targeting therapy by improving the quantity and quality of the EAAs.
authors.affiliation: Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, 30068, Taiwan, Republic of China.|Center for Bioinformatics Research, National Chiao Tung University, Hsinchu, 30068, Taiwan, Republic of China.
authors.forename: Yu-Ling
authors.initials: YL
authors.lastname: Lin
authors.affiliation: School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, 40201, Taiwan, Republic of China.|Clinical Laboratory, Chung Shan Medical University Hospital, Taichung 40201, Taiwan, Republic of China.
authors.forename: Nu-Man
authors.initials: NM
authors.lastname: Tsai
authors.affiliation: Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, 30068, Taiwan, Republic of China.
authors.forename: Cheng-Hao
authors.initials: CH
authors.lastname: Hsieh
authors.affiliation: Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, 30068, Taiwan, Republic of China.
authors.forename: Shu-Yi
authors.initials: SY
authors.lastname: Ho
authors.affiliation: Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, 30068, Taiwan, Republic of China.
authors.forename: Jung
authors.initials: J
authors.lastname: Chang
authors.affiliation: Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu, 30068, Taiwan, Republic of China.
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Wu
authors.affiliation: Nuclear Science & Technology Development Center, National Tsing Hua University, Hsinchu, 30013, Taiwan, Republic of China.
authors.forename: Ming-Hua
authors.initials: MH
authors.lastname: Hsu
authors.affiliation: Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, 30068, Taiwan, Republic of China.
authors.forename: Chia-Ching
authors.initials: CC
authors.lastname: Chang
authors.affiliation: Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, 30068, Taiwan, Republic of China; rhuang@jhu.edu liaonms@mail.nctu.edu.tw.|Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu, 30068, Taiwan, Republic of China.|Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan, Republic of China.
authors.forename: Kuang-Wen
authors.initials: KW
authors.lastname: Liao
authors.affiliation: Department of Biology, Johns Hopkins University, Baltimore, MD 21218-2685.
authors.forename: Tiffany L B
authors.initials: TL
authors.lastname: Jackson
authors.affiliation: Department of Biology, Johns Hopkins University, Baltimore, MD 21218-2685.
authors.forename: David E
authors.initials: DE
authors.lastname: Mold
authors.affiliation: Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, 30068, Taiwan, Republic of China; rhuang@jhu.edu liaonms@mail.nctu.edu.tw.|Department of Biology, Johns Hopkins University, Baltimore, MD 21218-2685.
authors.forename: Ru Chih C
authors.initials: RC
authors.lastname: Huang
mesh_terms: D028341:Activins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000912:Antibodies, Neoplasm / Q000097:blood; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001323:Autoantibodies / Q000097:blood; D053264:B-Cell Activating Factor / Q000235:genetics / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D004851:Epoxide Hydrolases / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D056724:Immunity, Humoral / Q000187:drug effects; D007155:Immunologic Factors / Q000008:administration & dosage*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010647:Phenyl Ethers / Q000008:administration & dosage*; D010880:Piperidines / Q000008:administration & dosage*; D015398:Signal Transduction; D047368:Tumor Burden
chemical_list: C501883:2,3-dimethyl-1,4-bis(3,4-(3-(piperdino)ethoxyphenyl))butane; D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; D001323:Autoantibodies; D053264:B-Cell Activating Factor; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D007155:Immunologic Factors; D010647:Phenyl Ethers; D010880:Piperidines; C505720:Tnfsf13b protein, mouse; C422405:activin A; D028341:Activins; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase
keywords: B-cell proliferation; P4N; cancer immunotherapy; colorectal cancer; endogenous antitumor autoantibody