Induction of endoplasmic reticulum stress-mediated apoptosis and non-canonical autophagy by luteolin in NCI-H460 lung carcinoma cells.

Abstract

In this study, we investigated the anti-cancer effects of luteolin, a member of the flavonoid family, in NCI-H460 human lung carcinoma cells. It was shown that luteolin induces apoptotic cell death through modulating both the extrinsic pathway and intrinsic pathways, which are suppressed by z-VAD-fmk, indicating that luteolin triggers caspase-dependant apoptosis. Furthermore, we found that the α subunit of the eukaryotic initiation factor 2 (eIF2α/C/EBP homologous protein pathway, but not the c-Jun N-terminal kinase pathway, played a critical role in induction of apoptosis by luteolin. The data indicated that luteolin also induces autophagy; evidence for this is the accumulation of microtubule-associated protein light chain-3 (LC3) II protein, the increase of LC3 puncta as well as an enhanced autophagy flux. In addition, inhibiting autophagy by bafilomycin A1 reduced apoptotic cell death, suggesting that luteolin-induced autophagy functions as a cell death mechanism. Notably, the activated caspases that appeared with luteolin treatment cleaved Beclin-1, and the expression of LC3II remained the same even after cells were challenged with Beclin-1 siRNA, demonstrating that luteolin induces Beclin-1-independent autophagy. Taken together, our findings showed that luteolin triggers both endoplasmic reticulum stress-related apoptosis and non-canonical autophagy, which function as a cell death mechanism in NCI-H460 human lung cancer cells.

• Authors: Shin-Hyung Park, Hyun Soo Park, Jun Hyuk Lee, Gyoo Yong Chi, Gi-Young Kim, Sung-Kwon Moon, Young-Chae Chang, Jin Won Hyun, Wun-Jae Kim, Yung Hyun Choi
• Journal: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association (Food Chem Toxicol) Vol. 56 Pg. 100-9 (Jun 2013) ISSN: 1873-6351 [Electronic] England
• PMID: 23454208 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• Amino Acid Chloromethyl Ketones
• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• BECN1 protein, human
• Beclin-1
• CCAAT-Enhancer-Binding Proteins
• Eukaryotic Initiation Factor-2
• MAP1LC3A protein, human
• Macrolides
• Membrane Proteins
• Microtubule-Associated Proteins
• RNA, Small Interfering
• benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
• bafilomycin A1
• JNK Mitogen-Activated Protein Kinases
• Luteolin

Topics

• Amino Acid Chloromethyl Ketones (pharmacology)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Autophagy (drug effects)
• Beclin-1
• CCAAT-Enhancer-Binding Proteins (genetics, metabolism)
• Cell Line, Tumor
• DNA Fragmentation
• Endoplasmic Reticulum Stress (drug effects)
• Eukaryotic Initiation Factor-2 (genetics, metabolism)
• Humans
• JNK Mitogen-Activated Protein Kinases (genetics, metabolism)
• Lung Neoplasms (pathology)
• Luteolin (pharmacology)
• Macrolides (pharmacology)
• Membrane Proteins (genetics, metabolism)
• Microtubule-Associated Proteins (genetics, metabolism)
• RNA, Small Interfering (genetics, isolation & purification)