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

Abstract

// Hye Lim Lee 1, * , Mi Hee Park 1, * , Dong Ju Son 1 , Ho Sueb Song 2 , Jung Hyun Kim 2 , Seong Cheol Ko 2 , Min Jong Song 3 , Won Hyoung Lee 4 , Joo Hee Yoon 5 , Young Wan Ham 6 , Sang Bae Han 1 , Jin Tae Hong 1 1 College of Pharmacy, Medical Research Center, Chungbuk National University, Osong-eup, Heungduk-gu, Cheongju, Chungbuk, Republic of Korea 2 Department of Acupuncture & Moxibustion Medicine, College of Korean Medicine, Gachon University, Bokjeong-dong, Sujeong-gu, Seongnam, Gyeonggii, Republic of Korea 3 Department of Obstetrics and Gynecology, Daejeon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Jung-gu, Daejeon Republic of Korea 4 Department of Nuclear Medicine Chungbuk National University Hospital, Seowon, Cheongju, Chungbuk Republic of Korea 5 Department of Obstetrics and Gynecology, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Paldal-gu, Suwon, Gyeonggi-do, Republic of Korea 6 Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah, United States * These authors have contributed equally to this work Correspondence to: Jin Tae Hong, e-mail: jinthong@chungbuk.ac.kr Sang Bae Han, e-mail: shan@chungbuk.ac.kr Keywords: snake venom toxin, apoptosis, PRDX6, AP-1, lung cancer Received: April 05, 2015      Accepted: May 20, 2015      Published: June 01, 2015 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.