Weng Ningna, Lv Sujuan, Chen Hong, Zheng Hanchen, Lin Tong, Zhu Qing, Zhu Kai, Huang Sha
Department of Medical Oncology, Fujian Cancer Hospital, Clinical Oncology School of Fujian Medical University, Fujian, 350011, PR China.
Hematology and Rheumatology Department, Chengdu Second People's Hospital, Sichuan, 610021, PR China.
Sci Rep. 2024 Dec 4;14(1):30163. doi: 10.1038/s41598-024-81911-z.
Pancreatic cancer (PC) is one of the most aggressive malignancies worldwide, and few effective therapeutics are available. Osthole (OST), a natural coumarin, has been proven to be a potential anticancer compound. In this study, we found that OST significantly inhibited PC growth both in vitro and in vivo. Notably, the anti-PC effect of OST is mediated by excessive autophagosome accumulation and consequent apoptosis in PC cells. Mechanistically, OST increased the number of autophagosomes via two pathways. First, OST induced autophagy initiation by suppressing the Akt/mTOR signaling pathway. Second, OST induced autophagic arrest by blocking autophagosome-lysosome fusion. Consistently, inhibition of autophagy initiation restored PC cell growth, whereas autophagic flux inhibitors exacerbated the antitumor effect of OST in PC cells, suggesting a cytotoxic role of OST-induced autophagosome accumulation. In addition, we found that OST upregulates the expression of activating transcription factor 3 (ATF3), resulting in inactivation of the Akt/mTOR signaling pathway and autophagy initiation in PC cells. ATF3 overexpression increased the activation of autophagy, and inhibition of ATF3 expression decreased autophagy. Taken together, our study provides new insights into the OST-induced growth inhibitory effect on PC cells, suggesting a promising potential therapeutic role of OST for PC treatment.
胰腺癌（PC）是全球最具侵袭性的恶性肿瘤之一，且有效的治疗方法很少。蛇床子素（OST）是一种天然香豆素，已被证明是一种潜在的抗癌化合物。在本研究中，我们发现OST在体外和体内均能显著抑制PC的生长。值得注意的是，OST对PC的抗癌作用是由PC细胞中自噬体过度积累及随后的凋亡介导的。机制上，OST通过两条途径增加自噬体的数量。首先，OST通过抑制Akt/mTOR信号通路诱导自噬起始。其次，OST通过阻断自噬体-溶酶体融合诱导自噬停滞。一致地，抑制自噬起始可恢复PC细胞生长，而自噬流抑制剂可增强OST对PC细胞的抗肿瘤作用，提示OST诱导的自噬体积累具有细胞毒性作用。此外，我们发现OST上调激活转录因子3（ATF3）的表达，导致PC细胞中Akt/mTOR信号通路失活和自噬起始。ATF3过表达增加自噬激活，而抑制ATF3表达则降低自噬。综上所述，我们的研究为OST对PC细胞的生长抑制作用提供了新的见解，提示OST在PC治疗中具有潜在的治疗作用。
