Anti-cancer effect of novel PAK1 inhibitor via induction of PUMA-mediated cell death and p21-mediated cell cycle arrest
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Tae-Gyun Woo1, Min-Ho Yoon1, Shin-Deok Hong1, Jiyun Choi2, Nam-Chul Ha3, Hokeun Sun2, Bum-Joon Park1
1Department of Molecular Biology, Pusan National University, Busan, Republic of Korea
2Department of Statistics, Pusan National University, Busan, Republic of Korea
3College of Agriculture and Life Sciences, Seoul National University, Seoul, Republic of Korea
Bum-Joon Park, email: firstname.lastname@example.org
Keywords: PAK1, anti-cancer, p21, PUMA, Bcl-2
Received: June 20, 2016 Accepted: February 06, 2017 Published: February 28, 2017
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 modulator of apoptosis) through direct binding and phosphorylation. On the basis of this result, we have tried to find novel PAK1-PUMA binding inhibitors. Through ELISA-based blind chemical library screening, we isolated single compound, IPP-14 (IPP; Inhibitor of PAK1-PUMA), which selectively blocks the PAK1-PUMA binding 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 kinase inactivation 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.
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