Camptothecin (CPT) from Camptotheca acuminate was discovered for anticancer drugs, which targets topoisomease I. However, whether CPT regulates c-Myc expression has not been understood in endoplasmic reticulum (ER) stress and autophagy. In this study, we found that CPT enhanced c-Myc expression and that the transient knockdown of c-Myc abrogated reactive oxygen species (ROS) generation, which resulted in the accumulation of ER stress-regulating proteins, such as PERK, eIF2α, ATF4, and CHOP. Moreover, the transfection of eIF2α-targeted siRNA attenuated CPT-induced autophagy and decreased the levels of Beclin-1 and Atg7, which indicated that CPT upregulated ER stress-mediated autophagy. In addition, CPT phosphorylated AMPK in response to intracellular Ca²⁺ release. Ca²⁺ chelators, ethylene glycol tetraacetic acid and a CaMKII inhibitor, K252a, decreased CPT-induced Beclin-1 and Atg7, and downregulated AMPK phosphorylation, which suggested that CPT-induced Ca²⁺ release leads to the activation of autophagy through CaMKII-mediated AMPK phosphorylation. CPT also phosphorylated JNK and activated the DNA-binding activity of AP-1; furthermore, knockdown of JNK abolished the expression level of Beclin-1 and Atg7, which implied that the JNK-AP-1 pathway was a potent mediator of CPT-induced autophagy. Our findings indicated that CPT promoted c-Myc-mediated ER stress and ROS generation, which enhances autophagy via the Ca²⁺-AMPK and JNK-AP-1 pathways.

已发现来自喜树的喜树碱（CPT）用于抗癌药物，其靶向拓扑异构酶I。但是，在内质网（ER）应激和自噬中尚不清楚CPT是否调节c-Myc表达。在这项研究中，我们发现，CPT增强c-Myc的表达和的瞬时敲低的c-Myc废除活性氧物质（ROS）的产生，这导致在ER应激调节蛋白，如PERK，eIF2α的，ATF4的积累和CHOP。此外，以eIF2α为靶标的siRNA的转染减弱了CPT诱导的自噬，并降低了Beclin-1和Atg7的水平，这表明CPT上调了ER应激介导的自噬。此外，CPT响应细胞内钙而使AMPK磷酸化²⁺版本。Ca ²⁺螯合剂乙二醇四乙酸和CaMKII抑制剂K252a降低了CPT诱导的Beclin-1和Atg7的表达，并下调了AMPK磷酸化，这表明CPT诱导的Ca ²⁺释放导致通过CaMKII-激活自噬。介导的AMPK磷酸化。CPT还使JNK磷酸化并激活AP-1的DNA结合活性。此外，敲除JNK消除了Beclin-1和Atg7的表达水平，这暗示JNK-AP-1途径是CPT诱导自噬的有效介体。我们的发现表明，CPT促进了c-Myc介导的内质网应激和ROS的产生，从而通过Ca ²⁺ -AMPK和JNK-AP-1途径增强了自噬。