In vivo amelioration of endogenous antitumor autoantibodies via low-dose P4N through the LTA4H/activin A/BAFF pathway

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题名:	In vivo amelioration of endogenous antitumor autoantibodies via low-dose P4N through the LTA4H/activin A/BAFF pathway
作者:	吳忻怡;Lin, Yu-Ling;Tsai, Nu-Man;Hsieh, Cheng-Hao;Ho, Shu-Yi;Chang, Jung;Wu, Hsin-Yi;Hsu, Ming-Hua;Chang, Chia-Ching;Liao, Kuang-Wen;Jackson, Tiffany L. B.;Mold, David E.;Huang, Ru Chih C.
贡献者:	總教學中心通識教育中心
日期:	2016-11-29
上传时间:	2026-04-23 12:53:08 (UTC+8)
出版者:	National Academy of Sciences
摘要:	摘要： This study finds that a small-molecule drug (P 4 N) is able to inhibit tumor growth by augmentation of endogenous antitumor autoantibodies (EAAs). We show that the enhancement of EAA activity by P 4 N is mediated through activation of the leukotriene A4 hydrolase (LTA4H)/activin A/B-cell activating factor (BAFF) pathway, revealing a valuable method for developing new immune modulators of tumor growth via humoral immunity. Typically, the effects of the humoral response on tumor inhibition are modest; however, the results of this study demonstrate that by removing the impediment to cancer cell destruction posed by low-activity autoantibodies, the realization of new, more potent immunotherapies for cancer treatment may be possible. 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 P 4 N, 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 P 4 N improved the quantity and quality of EAAs, and passive transfer of P 4 N-induced EAAs dramatically suppressed lung metastasis formation and prolonged the survival of mice inoculated with metastatic CT26 tumor cells. P 4 N-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, P 4 N 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, P 4 N 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. 出版日期： 2016-11-29 出處： Proceedings of the National Academy of Sciences - PNAS, 2016-11, Vol.113 (48) 資源來源： JSTOR Life Sciences Collection 識別號： ISSN: 0027-8424 識別號： EISSN: 1091-6490 識別號： DOI: 10.1073/pnas.1604752113
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