Abstract
Hepatocellular carcinoma (HCC) is one of the major malignancies worldwide and is associated with poor prognosis due to the high incidences of metastasis and tumor recurrence. Our previous study showed that overexpression of p21-activated protein kinase 1 (PAK1) is frequently observed in HCC and is associated with a more aggressive tumor behavior, suggesting that PAK1 is a potential therapeutic target in HCC. In the current study, an allosteric small molecule PAK1 inhibitor, IPA-3, was evaluated for the potential in suppressing hepatocarcinogenesis. Consistent with other reports, inhibition of PAK1 activity was observed in several human HCC cell lines treated with various dosages of IPA-3. Using cell proliferation, colony formation and BrdU incorporation assays, we demonstrated that IPA-3 treatment significantly inhibited the growth of HCC cells. The mechanisms through which IPA-3 treatment suppresses HCC cell growth are enhancement of apoptosis and blockage of activation of NF-κB. Furthermore, our data suggested that IPA-3 not only inhibits the HCC cell growth, but also suppresses the metastatic potential of HCC cells. Nude mouse xenograft assay demonstrated that IPA-3 treatment significantly reduced the tumor growth rate and decreased tumor volume, indicating that IPA-3 can suppress the in vivo tumor growth of HCC cells. Taken together, our demonstration of the potential preclinical efficacy of IPA-3 in HCC provides the rationale for cancer therapy.
Highlights
As the sixth most common malignant tumor and the third leading cause of cancer mortality worldwide, hepatocellular carcinoma (HCC) is responsible for more than a million deaths annually [1]
With little or less reports of IPA-3 in the treatment of human HCC, we employed various in vitro and in vivo experiments to investigate the antitumorigenic ability of IPA-3 treatment on human HCC cell lines
We demonstrated that IPA-3 could inhibit the proliferation rate of HepG2, H2P, H2M, and MHCC97L cells in dose- and time-dependent manners
Summary
As the sixth most common malignant tumor and the third leading cause of cancer mortality worldwide, hepatocellular carcinoma (HCC) is responsible for more than a million deaths annually [1]. HCC is associated with poor prognosis due to high incidences of tumor recurrence and metastasis [2]. Overexpression of p21-activated kinase 1 (PAK1) is frequent in HCC [4]. It is a downstream effector of the small Rho GTPase, including Rac and Cdc, which regulates diverse cellular processes, including cell cycle progression, cell motility, cell polarity and apoptosis [5]. Activated Rho GTPase binds to PAKs on the Cdc42/Rac interactive binding (CRIB) domain, causing the relief of autoinhibitory domain (AID), subsequent autophosphorylation of the catalytic domain and kinase activation [6]. Among the multiple autophosphorylation sites, threonine-423 (T423) is important for counteracting autoinhibition and maintaining the complete activated state [7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
