Anti-cancer effect of novel PAK1 inhibitor via induction of PUMA-mediated cell death and p21-mediated cell cycle arrest

// Tae-Gyun Woo 1 , Min-Ho Yoon 1 , Shin-Deok Hong 1 , Jiyun Choi 2 , Nam-Chul Ha 3 , Hokeun Sun 2 , Bum- JoonPark 1 1 Department of Molecular Biology, Pusan National University, Busan, Republic of Korea 2 Department of Statistics, Pusan National University, Busan, Republic of Korea 3 College of Agriculture and Life Sciences, Seoul National University, Seoul, Republic of Korea Correspondence to: Bum- JoonPark, email: bjpark1219@pusan.ac.kr Keywords: PAK1, anti-cancer, p21, PUMA, Bcl-2 Received: June 20, 2016 Accepted: February 06, 2017 Published: February 28, 2017 ABSTRACT Hyper-activation of PAK1 (p21-activated kinase 1) is frequently observed in human cancer and speculated as a target of novel anti-tumor drug. In previous, we also showed that PAK1 is highly activated in the Smad4-deficient condition and suppresses PUMA( p53 upregulated modulatorof apoptosis) through direct binding and phosphorylation. On the basis of this result, we have tried to find novel PAK1- PUMAbinding inhibitors. Through ELISA-based blind chemical libraryscreening, we isolated single compound, IPP-14 (IPP; Inhibitor of PAK1- PUMA), which selectively blocks the PAK1- PUMAbinding and also suppresses cell proliferation via PUMA-dependent manner. Indeed, in PUMA-deficient cells, this chemical did not show anti-proliferating effect. This chemical possessed very strong PAK1 inhibition activity that it suppressed BAD (Bcl-2-asoociated death promoter) phosphorylation and meta-phase arrest via Aurora kinaseinactivation in lower concentration than that of previous PAK1 kinase, FRAX486 and AG879. Moreover, our chemical obviously induced p21/WAF1/CIP1 (Cyclin-dependent kinase inhibitor 1A) expression by releasing from Bcl-2 (B-cell lymphoma-2) and by inhibition of AKT-mediated p21 suppression. Considering our result, IPP-14 and its derivatives would be possible candidates for PAK1 and p21 induction targeted anti-cancer drug.