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
  • 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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