Crebanine, an aporphine alkaloid, sensitizes TNF-α-induced apoptosis and suppressed invasion of human lung adenocarcinoma cells A549 by blocking NF-κB-regulated gene products.

Abstract

Crebanine is an alkaloid known to exhibit anticancer, but its mechanism is not well understood. Besides, the nuclear factor-kappa B (NF-κB) transcription factor has been correlated with inflammation, carcinogenesis, tumor cell survival, invasion, and angiogenesis. In this study, we investigated the effects of crebanine on tumor necrosis factor alpha (TNF-α)-induced NF-κB activation and the expression of NF-κB-regulated gene products. We found that crebanine reduced the cell proliferation of lung, ovarian, and breast cancer cells. Crebanine also potentiated TNF-α-induced apoptosis which correlated with the suppression of the gene products linked to cell survival, B cell lymphoma-extra large, and proliferation, cyclin D1. In addition, crebanine affected TNF-α-induced activation of caspase-8, caspase-3, and poly(ADP-ribose) polymerase cleavage, indicating that the apoptotic effects of TNF-α were enhanced by crebanine. Moreover, crebanine reduced TNF-α-induced A549 cell invasion and migration. Furthermore, crebanine suppressed the TNF-α-mediated expression of proteins that involved cancer cell invasion (matrix metalloproteinase 9 urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor and intercellular adhesion molecule 1) and angiogenesis (COX-2 and VEGF), all of which are known to be regulated by NF-κB. We also demonstrated that TNF-α induced NF-κB DNA-binding activity, which was inhibited by crebanine. Moreover, crebanine suppressed the TNF-α-induced degradation of inhibitor of NF-κB alpha (IκBa), which led to reduced NF-κB translocation to the nucleus. Taken together, our results demonstrated that crebanine reduced TNF-α-induced cancer cell proliferation, invasion, and survival by suppressing NF-κB activity and expression profile of its downstream genes.

• Authors: Supachai Yodkeeree, Wilart Pompimon, Pornngarm Limtrakul
• Journal: Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine (Tumour Biol) Vol. 35 Issue 9 Pg. 8615-24 (Sep 2014) ISSN: 1423-0380 [Electronic] Netherlands
• PMID: 24867094 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aporphines
• BCL2L1 protein, human
• I-kappa B Proteins
• NF-kappa B
• Tumor Necrosis Factor-alpha
• bcl-X Protein
• Cyclin D1
• crebanine
• Poly(ADP-ribose) Polymerases
• Caspase 3
• Caspase 8

Topics

• Adenocarcinoma (metabolism, pathology)
• Animals
• Apoptosis (drug effects)
• Aporphines (pharmacology)
• Blotting, Western
• Caspase 3 (metabolism)
• Caspase 8 (metabolism)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cyclin D1 (metabolism)
• Dose-Response Relationship, Drug
• Drug Synergism
• Humans
• I-kappa B Proteins (metabolism)
• Lung Neoplasms (metabolism, pathology)
• MCF-7 Cells
• Mice
• NF-kappa B (metabolism)
• NIH 3T3 Cells
• Neoplasm Invasiveness
• Poly(ADP-ribose) Polymerases (metabolism)
• Tumor Necrosis Factor-alpha (pharmacology)
• bcl-X Protein (metabolism)