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

Yu Ling Lin, Nu Man Tsai, Cheng Hao Hsieh, Shu Yi Ho, Jung Chang, Hsin Yi Wu, Ming Hua Hsu, Chia Ching Chang, Kuang Wen Liao, Tiffany L.B. Jackson, David E. Mold, Ru Chih C. Huang

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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.

Original languageEnglish
Pages (from-to)E7798-E7807
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number48
DOIs
Publication statusPublished - 2016 Nov 29

All Science Journal Classification (ASJC) codes

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    Lin, Y. L., Tsai, N. M., Hsieh, C. H., Ho, S. Y., Chang, J., Wu, H. Y., Hsu, M. H., Chang, C. C., Liao, K. W., Jackson, T. L. B., Mold, D. E., & Huang, R. C. C. (2016). In vivo amelioration of endogenous antitumor autoantibodies via low-dose P4N through the LTA4H/activin A/BAFF pathway. Proceedings of the National Academy of Sciences of the United States of America, 113(48), E7798-E7807. https://doi.org/10.1073/pnas.1604752113