Kim Cho-Long, Lim Su-Bin, Kim Dong Hyun, Sim Ye Eun, Kang Li-Jung, Park Su Jung, Kim Hyungwoo, Roh Tae Hoon, Mo Jung-Soon, Jeong Han-Sol
Department of Biomedical Sciences, Graduate School, Ajou University School of Medicine, Suwon 16499, South Korea.
Three-Dimensional Immune System Imaging Core Facility, Ajou University, Suwon 16499, South Korea.
Transl Oncol. 2024 Aug;46:101971. doi: 10.1016/j.tranon.2024.101971. Epub 2024 May 25.
Cholangiocarcinoma (CCA) is a devastating malignancy characterized by aggressive tumor growth and limited treatment options. Dysregulation of the Hippo signaling pathway and its downstream effector, Yes-associated protein (YAP), has been implicated in CCA development and progression. In this study, we investigated the effects of Isoalantolactone (IALT) on CCA cells to elucidate its effect on YAP activity and its potential clinical significance. Our findings demonstrate that IALT exerts cytotoxic effects, induces apoptosis, and modulates YAP signaling in SNU478 cells. We further confirmed the involvement of the canonical Hippo pathway by generating LATS1/LATS2 knockout cells, highlighting the dependence of IALT-mediated apoptosis and YAP phosphorylation on the Hippo-LATS signaling axis. In addition, IALT suppressed cell growth and migration, partially dependent on YAP-TEAD activity. These results provide insights into the therapeutic potential of targeting YAP in CCA and provide a rationale for developing of YAP-targeted therapies for this challenging malignancy.
胆管癌（CCA）是一种具有侵袭性肿瘤生长和有限治疗选择的毁灭性恶性肿瘤。Hippo信号通路及其下游效应分子Yes相关蛋白（YAP）的失调与CCA的发生和发展有关。在本研究中，我们研究了异土木香内酯（IALT）对CCA细胞的影响，以阐明其对YAP活性的作用及其潜在的临床意义。我们的研究结果表明，IALT对SNU478细胞具有细胞毒性作用，诱导细胞凋亡，并调节YAP信号。我们通过生成LATS1/LATS2基因敲除细胞进一步证实了经典Hippo通路的参与，突出了IALT介导的细胞凋亡和YAP磷酸化对Hippo-LATS信号轴的依赖性。此外，IALT抑制细胞生长和迁移，部分依赖于YAP-TEAD活性。这些结果为在CCA中靶向YAP的治疗潜力提供了见解，并为开发针对这种具有挑战性的恶性肿瘤的YAP靶向治疗提供了理论依据。
