2. Academic Validation
  3. An alkaloid initiates phosphodiesterase 3A-schlafen 12 dependent apoptosis without affecting the phosphodiesterase activity

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

  • Nat Commun. 2020 Jun 26;11(1):3236. doi: 10.1038/s41467-020-17052-4.
Youwei Ai 1 2 3,  Haibing He 4,  Peihao Chen 5 6,  Bo Yan 5 6,  Wenbin Zhang 5 6,  Zhangcheng Ding 5 6,  Dianrong Li 5 6,  Jie Chen 5,  Yan Ma 5,  Yang Cao 5,  Jie Zhu 5,  Jiaojiao Li 5,  Jinjie Ou 4,  Shan Du 4,  Xiaodong Wang 5 6,  Jianzhang Ma 7,  Shuanhu Gao 8,  Xiangbing Qi 9 10
Affiliations

Affiliations

  • 1 College of Wildlife and Protected Area, Northeast Forestry University, Hexing Road, 150040, Harbin, China. [email protected].
  • 2 National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, 102206, Beijing, China. [email protected].
  • 3 Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China. [email protected].
  • 4 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University, 3663N Zhongshan Road, 200062, Shanghai, China.
  • 5 National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, 102206, Beijing, China.
  • 6 Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China.
  • 7 College of Wildlife and Protected Area, Northeast Forestry University, Hexing Road, 150040, Harbin, China. [email protected].
  • 8 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University, 3663N Zhongshan Road, 200062, Shanghai, China. [email protected].
  • 9 National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, 102206, Beijing, China. [email protected].
  • 10 Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China. [email protected].
PMID: 32591543 DOI: 10.1038/s41467-020-17052-4
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.

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