Anti-cancer effect of snake venom toxin through down regulation of AP-1 mediated PRDX6 expression.

Abstract

Snake venom toxin (SVT) from Vipera lebetina turanica contains a mixture of different enzymes and proteins. Peroxiredoxin 6 (PRDX6) is known to be a stimulator of lung cancer cell growth. PRDX6 is a member of peroxidases, and has calcium-independent phospholipase A2 (iPLA2) activities. PRDX6 has an AP-1 binding site in its promoter region of the gene. Since AP-1 is implicated in tumor growth and PRDX6 expression, in the present study, we investigated whether SVT inhibits PRDX6, thereby preventing human lung cancer cell growth (A549 and NCI-H460) through inactivation of AP-1. A docking model study and pull down assay showed that SVT completely fits on the basic leucine zipper (bZIP) region of c-Fos of AP-1. SVT (0-10 μg/ml) inhibited lung cancer cell growth in a concentration dependent manner through induction of apoptotic cell death accompanied by induction of cleaved caspase-3, -8, -9, Bax, p21 and p53, but decreased cIAP and Bcl2 expression via inactivation of AP-1. In an xenograft in vivo model, SVT (0.5 mg/kg and 1 mg/kg) also inhibited tumor growth accompanied with the reduction of PRDX6 expression, but increased expression of proapoptotic proteins. These data indicate that SVT inhibits tumor growth via inhibition of PRDX6 activity through interaction with its transcription factor AP-1.

• Authors: Hye Lim Lee, Mi Hee Park, Dong Ju Son, Ho Sueb Song, Jung Hyun Kim, Seong Cheol Ko, Min Jong Song, Won Hyoung Lee, Joo Hee Yoon, Young Wan Ham, Sang Bae Han, Jin Tae Hong
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 26 Pg. 22139-51 (Sep 08 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26061816 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Snake Venoms
• Transcription Factor AP-1
• PRDX6 protein, human
• Peroxiredoxin VI

Topics

• Animals
• Apoptosis (drug effects)
• Cell Line, Tumor
• Down-Regulation (drug effects)
• Humans
• Lung Neoplasms (drug therapy, genetics, metabolism, pathology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Molecular Docking Simulation
• Peroxiredoxin VI (antagonists & inhibitors, biosynthesis, genetics, metabolism)
• Snake Venoms (chemistry, pharmacology)
• Transcription Factor AP-1 (genetics, metabolism)
• Transfection
• Xenograft Model Antitumor Assays