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.

促进肿瘤细胞凋亡是开发抗癌药物的流行策略。在这里，我们证明植物吲哚生物碱天然产物 nauclefine 通过 PDE3A-SLFN12 依赖性死亡途径诱导多种癌细胞凋亡。 Nauclefine 结合 PDE3A，但不抑制 PDE3A 的磷酸二酯酶活性，因此代表一种以前未知的 PDE3A 调节剂类型，可以启动细胞凋亡而不影响 PDE3A 的典型功能。我们证明 PDE3A 的 H840、Q975、Q1001 和 F1004 残基以及 SLFN12 中的 I105 对于核酸诱导的 PDE3A-SLFN12 相互作用和细胞死亡至关重要。扩展这些分子见解，我们在体内证明 nauclefine 以 PDE3A 和 SLFN12 依赖性方式抑制肿瘤异种移植物生长。因此，除了证明生物碱天然产物的有效细胞毒性作用之外，我们的研究还说明了一种潜在的减少副作用的策略，用于靶向 PDE3A 进行抗癌治疗，而不影响其磷酸二酯酶活性。