Anti-Tumor Activity of Yuanhuacine by Regulating AMPK/mTOR Signaling Pathway and Actin Cytoskeleton Organization in Non-Small Cell Lung Cancer Cells.

Abstract

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.

• Authors: Ji In Kang, Ji-Young Hong, Hye-Jung Lee, Song Yi Bae, Cholomi Jung, Hyen Joo Park, Sang Kook Lee
• Journal: PloS one (PLoS One) Vol. 10 Issue 12 Pg. e0144368 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 26656173 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• Diterpenes
• Quinazolines
• Yuanhuacin
• TOR Serine-Threonine Kinases
• AMP-Activated Protein Kinases
• Gefitinib
• Sirolimus

Topics

• AMP-Activated Protein Kinases (metabolism)
• Actin Cytoskeleton (drug effects, metabolism)
• Animals
• Antineoplastic Agents (pharmacology)
• Biomarkers, Tumor (metabolism)
• Carcinoma, Non-Small-Cell Lung (enzymology, pathology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Diterpenes (pharmacology)
• Female
• Gefitinib
• Humans
• Lung Neoplasms (enzymology, pathology)
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Invasiveness
• Quinazolines (pharmacology)
• Signal Transduction (drug effects)
• Sirolimus (pharmacology)
• TOR Serine-Threonine Kinases (metabolism)
• Xenograft Model Antitumor Assays