An alkaloid initiates phosphodiesterase 3A–schlafen 12 dependent apoptosis without affecting the phosphodiesterase activity
| Autor: | Zhangcheng Ding, Wenbin Zhang, Yan Ma, Bo Yan, Yang Cao, Jianzhang Ma, Jiaojiao Li, Peihao Chen, Xiangbing Qi, Jinjie Ou, Jie Chen, Haibing He, Dianrong Li, Shan Du, Jie Zhu, Xiaodong Wang, Youwei Ai, Shuanhu Gao |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Programmed cell death Indoles Cell Survival Science General Physics and Astronomy Mice Nude Apoptosis Phosphodiesterase 3 Inhibitors 01 natural sciences General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences chemistry.chemical_compound Alkaloids In vivo Target identification Cell Line Tumor Tetrahydroisoquinolines Cytotoxic T cell Animals Humans Naphthyridines lcsh:Science Cell Proliferation Multidisciplinary Natural product 010405 organic chemistry Protein Stability Intracellular Signaling Peptides and Proteins Phosphodiesterase General Chemistry Xenograft Model Antitumor Assays Cyclic Nucleotide Phosphodiesterases Type 3 0104 chemical sciences Cell biology Cilostazol 030104 developmental biology chemistry Cell culture Cancer cell Female lcsh:Q |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-10 (2020) Nature Communications |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-020-17052-4 |
| Popis: | 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. PDE3A modulators for cancer therapy cause serious side effects as they inhibit PDE3A phosphodiesterase activity, which is essential for the maturation of oocytes and the formation of platelets. Here, the authors identify a compound, nauclefine, that does not inhibit PDE3A activity but induces apoptosis by enabling a complex formation between PDE3A and SLFN12. |
| Databáze: | OpenAIRE |
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