Sterol regulatory element-binding proteins (SREBPs) are master transcriptional regulators of the mevalonate pathway and lipid metabolism and represent an attractive therapeutic target for lipid metabolic disorders. SREBPs are maintained in the endoplasmic reticulum (ER) in a tripartite complex with SREBP cleavage-activating protein (SCAP) and insulin-induced gene protein (INSIG). When new lipid synthesis is required, the SCAP-SREBP complex dissociates from INSIG and undergoes ER-to-Golgi transport where the N-terminal transcription factor domain is released by proteolysis. The mature transcription factor translocates to the nucleus and stimulates expression of the SREBP gene program. Previous studies showed that dipyridamole, a clinically prescribed phosphodiesterase (PDE) inhibitor, potentiated statin-induced tumor growth inhibition. Dipyridamole limited nuclear accumulation of SREBP, but the mechanism was not well resolved. In this study, we show that dipyridamole selectively blocks ER-to-Golgi movement of the SCAP-SREBP complex and that this is independent of its PDE inhibitory activity.

甾醇调节元件结合蛋白 (SREBPs) 是甲羟戊酸途径和脂质代谢的主要转录调节因子，代表了脂质代谢紊乱的有吸引力的治疗靶点。SREBP 维持在内质网 (ER) 中与 SREBP 裂解激活蛋白 (SCAP) 和胰岛素诱导基因蛋白 (INSIG) 形成三重复合体。当需要新的脂质合成时，SCAP-SREBP 复合物从 INSIG 解离并经历 ER 到高尔基体的转运，其中 N 端转录因子结构域通过蛋白水解释放。成熟的转录因子易位到细胞核并刺激 SREBP 基因程序的表达。先前的研究表明，双嘧达莫是一种临床处方磷酸二酯酶 (PDE) 抑制剂，可增强他汀类药物诱导的肿瘤生长抑制。双嘧达莫限制了 SREBP 的核积累，但该机制尚未得到很好的解决。在这项研究中，我们表明双嘧达莫选择性地阻止 SCAP-SREBP 复合物的 ER 到高尔基体的运动，并且这与其 PDE 抑制活性无关。