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 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.
Highlights
Elevated expression of PAK1 (p21-activated kinase 1) is frequently observed in various kinds of human cancers including colon or pancreatic cancers [1, 2]
We revealed that serumstarvation-induced cell death can be activated by PUMA via Smad4-induced PAK1 inhibition
We confirmed the inhibitory effect on PAK1-PUMA binding through Glutathione S-transferase (GST) pull-down and Immunoprecipitation (IP) assay (Figure 1B and Supplementary Figure 1E)
Summary
Elevated expression of PAK1 (p21-activated kinase 1) is frequently observed in various kinds of human cancers including colon or pancreatic cancers [1, 2]. This kinase has been reported to be involved in broad oncogenic properties including anti-apoptosis, cell cycle promotion and metastasis. PAK1, activated by small GTP-proteins (such as cdc or Rac), can promote cell migration [3, 4], and can suppress the apoptosis through BAD phosphorylation [5,6,7]. We revealed that activation of PAK1 in Smad deficient cancers suppresses PUMAmediated apoptosis [11]. Considering that half of pancreatic cancers and more than 20% of colon cancers show deletion of Smad4 [12,13,14], inhibition of PAK1 would be one of plausible strategy for treatment of human cancers such as pancreatic cancer and colon cancer
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