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Effects of p21-activated kinase 1 inhibition on 11q13-amplified ovarian cancer cells.

ABSTRACT: p21-activated kinases (Paks) are Cdc42/Rac-activated serine-threonine protein kinases that regulate several key cancer-relevant signaling pathways, such as the Mek/Erk, PI3K/Akt and Wnt/b-catenin signaling pathways. Pak1 is frequently overexpressed and/or hyperactivated in different human cancers, including human breast, ovary, prostate and brain cancer, due to amplification of the PAK1 gene in an 11q13 amplicon. Genetic or pharmacological inactivation of Pak1 has been shown to reduce proliferation of different cancer cells in vitro and reduce tumor progression in vivo. In this work, we examined the roles of Pak1 in cellular and animal models of PAK1-amplified ovarian cancer. We found that inhibition of Pak1 leads to decreased proliferation and migration in PAK1-amplified/overexpressed ovarian cancer cells, and has no effect in cell that lack such amplification/overexpression. Further, we observed that loss of Pak1 function causes 11q13-amplified ovarian cancer cells to arrest in the G2/M phase of the cell cycle. This arrest correlates with activation of p53 and p21(Cip) and decreased expression of cyclin B1. These findings suggest that small-molecule inhibitors of Pak1 may have a therapeutic role in the ~25% of ovarian cancers characterized by PAK1 gene amplification.

SUBMITTER: Prudnikova TY

PROVIDER: S-EPMC5125076 | biostudies-other | 2016 Apr

REPOSITORIES: biostudies-other

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Effects of p21-activated kinase 1 inhibition on 11q13-amplified ovarian cancer cells.

Prudnikova T Y TY Villamar-Cruz O O Rawat S J SJ Cai K Q KQ Chernoff J J

Oncogene 20150810 17

p21-activated kinases (Paks) are Cdc42/Rac-activated serine-threonine protein kinases that regulate several key cancer-relevant signaling pathways, such as the Mek/Erk, PI3K/Akt and Wnt/b-catenin signaling pathways. Pak1 is frequently overexpressed and/or hyperactivated in different human cancers, including human breast, ovary, prostate and brain cancer, due to amplification of the PAK1 gene in an 11q13 amplicon. Genetic or pharmacological inactivation of Pak1 has been shown to reduce proliferat ...[more]

PMID: 26257058

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Project description:P21-activated kinase-1 (PAK-1) is a serine/threonine kinase involved in multiple signaling pathways that mediate cellular functions such as cytoskeletal motility, cell proliferation, and survival. PAK-1 expression is altered in various cancers, including prostate and breast. Our recent studies showed that prostate cancer cells expressing higher levels of PAK-1 were resistant to the cytotoxic effects of the PAK-1 inhibitor, inhibitor targeting PAK-1 activation-3 (IPA-3), compared to those with lower expression. This study expanded these findings to other cancers (breast and melanoma) by testing the hypothesis that genetic and pharmacological inhibition of PAK-1 alters cell growth, migration, and invasion in prostate, breast, and skin cancer cell lines. We also tested the specificity of IPA-3 for PAK-1 and the hypothesis that gene silencing of PAK-1 altered the efficacy of sterically stabilized liposomes (SSL) containing IPA-3 (SSL-IPA-3). PAK-1 expression was identified in four different breast cancer cell lines, and in a melanoma cell line. The expression of PAK-1 correlated to the IC50 of IPA-3 as measured by MTT staining. PAK-1 inhibition using shRNA correlated with decreased cell migration and invasion in prostate cancer DU-145 and breast cancer MCF-7 cells. Decreased migration and invasion also correlated to decreased expression of E-cadherin and alterations in C-X-C Chemokine Receptor type 4 and Homing Cell Adhesion Molecule expression. PAK-1 inhibition increased the cytotoxicity of IPA-3, and the cytotoxicity of SSL-IPA-3 to levels comparable to that of free drug. These data demonstrate that both pharmacological and molecular inhibition of PAK-1 decreased growth in prostate, breast, and melanoma cancer cell lines, and increased the toxicity of IPA-3 and its liposomal formulation. These data also show the specificity of IPA-3 for PAK-1, are some of the first data suggesting that IPA-3 is a therapeutic treatment for breast cancer and melanoma, and demonstrate the efficacy of liposome-encapsulated IPA-3 in breast cancer cells.

Dataset Information

Effects of p21-activated kinase 1 inhibition on 11q13-amplified ovarian cancer cells.

Publications

Effects of p21-activated kinase 1 inhibition on 11q13-amplified ovarian cancer cells.

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