Kang Ji In, Hong Ji-Young, Lee Hye-Jung, Bae Song Yi, Jung Cholomi, Park Hyen Joo, Lee Sang Kook
College of Pharmacy, Seoul National University, Seoul, 151-742, Republic of Korea.
PLoS One. 2015 Dec 11;10(12):e0144368. doi: 10.1371/journal.pone.0144368. eCollection 2015.
Yuanhuacine (YC), a daphnane diterpenoid from the flowers of Daphne genkwa, exhibited a potential growth inhibitory activity against human non-small cell lung cancer (NSCLC) cells. YC also suppressed the invasion and migration of lung cancer cells. However, the precise molecular mechanisms remain to be elucidated. In the present study, we report that YC significantly activated AMP-activated protein kinase (AMPK) signaling pathway and suppressed mTORC2-mediated downstream signaling pathway in H1993 human NSCLC cells. AMPK plays an important role in energy metabolism and cancer biology. Therefore, activators of AMPK signaling pathways can be applicable to the treatment of cancer. YC enhanced the expression of p-AMPKα. The co-treatment of YC and compound C (an AMPK inhibitor) or metformin (an AMPK activator) also confirmed that YC increases p-AMPKα. YC also suppressed the activation of the mammalian target of rapamycin (mTOR) expression, a downstream target of AMPK. Further study revealed that YC modulates mTORC2-associated downstream signaling pathways with a decreased expressions of p-Akt, p-protein kinase C alpha (PKCα), p-ras-related C3 botulinum toxin substrate 1 (Rac1) and filamentous actin (F-actin) that are known to activate cell growth and organize actin cytoskeleton. In addition, YC inhibited the tumor growth in H1993 cell-implanted xenograft nude mouse model. These data suggest the YC could be a potential candidate for cancer chemotherapeutic agents derived from natural products by regulating AMPK/mTORC2 signaling pathway and actin cytoskeleton organization.
芫花酯甲（YC）是一种从芫花的花中提取的瑞香烷二萜类化合物，对人非小细胞肺癌（NSCLC）细胞具有潜在的生长抑制活性。YC还抑制肺癌细胞的侵袭和迁移。然而，其确切的分子机制仍有待阐明。在本研究中，我们报道YC在H1993人NSCLC细胞中显著激活AMP激活的蛋白激酶（AMPK）信号通路，并抑制mTORC2介导的下游信号通路。AMPK在能量代谢和癌症生物学中发挥重要作用。因此，AMPK信号通路的激活剂可应用于癌症治疗。YC增强了p-AMPKα的表达。YC与化合物C（一种AMPK抑制剂）或二甲双胍（一种AMPK激活剂）的联合处理也证实YC增加了p-AMPKα。YC还抑制了雷帕霉素哺乳动物靶标（mTOR）表达的激活，mTOR是AMPK的下游靶标。进一步的研究表明，YC通过降低已知可激活细胞生长和组织肌动蛋白细胞骨架的p-Akt、p-蛋白激酶Cα（PKCα）、p-鼠肉瘤相关C3肉毒杆菌毒素底物1（Rac1）和丝状肌动蛋白（F-肌动蛋白）的表达来调节mTORC2相关的下游信号通路。此外，YC在H1993细胞植入的异种移植裸鼠模型中抑制了肿瘤生长。这些数据表明，YC可能是一种通过调节AMPK/mTORC2信号通路和肌动蛋白细胞骨架组织而从天然产物衍生的癌症化疗药物的潜在候选物。
