An alkaloid initiates phosphodiesterase 3A–schlafen 12 dependent apoptosis without affecting the phosphodiesterase activity

Youwei Ai (), Haibing He, Peihao Chen, Bo Yan, Wenbin Zhang, Zhangcheng Ding, Dianrong Li, Jie Chen, Yan Ma, Yang Cao, Jie Zhu, Jiaojiao Li, Jinjie Ou, Shan Du, Xiaodong Wang, Jianzhang Ma (), Shuanhu Gao () and Xiangbing Qi ()
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Youwei Ai: Northeast Forestry University
Haibing He: East China Normal University
Peihao Chen: National Institute of Biological Sciences
Bo Yan: National Institute of Biological Sciences
Wenbin Zhang: National Institute of Biological Sciences
Zhangcheng Ding: National Institute of Biological Sciences
Dianrong Li: National Institute of Biological Sciences
Jie Chen: National Institute of Biological Sciences
Yan Ma: National Institute of Biological Sciences
Yang Cao: National Institute of Biological Sciences
Jie Zhu: National Institute of Biological Sciences
Jiaojiao Li: National Institute of Biological Sciences
Jinjie Ou: East China Normal University
Shan Du: East China Normal University
Xiaodong Wang: National Institute of Biological Sciences
Jianzhang Ma: Northeast Forestry University
Shuanhu Gao: East China Normal University
Xiangbing Qi: National Institute of Biological Sciences

Nature Communications, 2020, vol. 11, issue 1, 1-10

Abstract: Abstract The promotion of apoptosis in tumor cells is a popular strategy for developing anti-cancer drugs. Here, we demonstrate that the plant indole alkaloid natural product nauclefine induces apoptosis of diverse cancer cells via a PDE3A-SLFN12 dependent death pathway. Nauclefine binds PDE3A but does not inhibit the PDE3A’s phosphodiesterase activity, thus representing a previously unknown type of PDE3A modulator that can initiate apoptosis without affecting PDE3A’s canonical function. We demonstrate that PDE3A’s H840, Q975, Q1001, and F1004 residues—as well as I105 in SLFN12—are essential for nauclefine-induced PDE3A-SLFN12 interaction and cell death. Extending these molecular insights, we show in vivo that nauclefine inhibits tumor xenograft growth, doing so in a PDE3A- and SLFN12-dependent manner. Thus, beyond demonstrating potent cytotoxic effects of an alkaloid natural product, our study illustrates a potentially side-effect-reducing strategy for targeting PDE3A for anti-cancer therapeutics without affecting its phosphodiesterase activity.

Date: 2020
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DOI: 10.1038/s41467-020-17052-4

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