雄激素信号仍然是处理晚期前列腺癌的关键治疗方法，然而，大多数肿瘤最终向侵袭性表型转变，该表型特征是雄激素无依赖性和治疗耐药性。环磷酸腺苷（cAMP）通路在调控多种细胞过程中起着至关重要的作用，磷酸二酯酶PDE4D7是前列腺癌细胞中cAMP信号的重要调节因子。通过使用shRNA介导的PDE4D7基因敲除在LNCaP细胞中，通过RNA测序和表型分析进行下游分析，我们复制了临床观察到的减少PDE4D7表达促进侵袭性前列腺癌表型的结果。我们的研究提供了证据，表明PDE4D7表达的丧失代表了从雄激素敏感状态向激素无反应性和神经内分泌分化状态转变的重要转变。此外，我们证明了PDE4D7丧失影响DNA修复通路，从而赋予对多聚腺苷二磷酸核糖聚合酶（PARP）抑制剂的耐药性。恢复PDE4D7表达可以使前列腺癌细胞对抗雄激素药物、DNA损伤反应抑制剂和细胞毒性治疗产生敏感性。这些发现为我们理解PDE4D7在致命性前列腺癌发展中的调控作用以及其作为一种新的治疗策略的潜力提供了重要见解。© 2023作者。

Androgen signalling remains the seminal therapeutic approach for the management of advanced prostate cancer. However, most tumours eventually shift towards an aggressive phenotype, characterised by androgen independence and treatment resistance. The cyclic adenosine monophosphate (cAMP) pathway plays a crucial role in regulating various cellular processes, with the phosphodiesterase PDE4D7 being a vital modulator of cAMP signalling in prostate cancer cells.Using shRNA-mediated PDE4D7 knockdown in LNCaP cells and downstream analysis via RNA sequencing and phenotypic assays, we replicate clinical observations that diminished PDE4D7 expression promotes an aggressive prostate cancer phenotype.Our study provides evidence that loss of PDE4D7 expression represents a pivotal switch driving the transition from an androgen-sensitive state to hormone unresponsiveness and neuroendocrine differentiation. In addition, we demonstrate that PDE4D7 loss affects DNA repair pathways, conferring resistance to poly ADP ribose polymerase (PARP) inhibitors.Reinstating PDE4D7 expression sensitises prostate cancer cells to anti-androgens, DNA damage response inhibitors, and cytotoxic therapies. These findings provide significant insight into the regulatory role of PDE4D7 in the development of lethal prostate cancer and the potential of its modulation as a novel therapeutic strategy.© 2023. The Author(s).