Development of p21 Activated Kinase-Targeted Multikinase Inhibitors That Inhibit Thyroid Cancer Cell Migration

Ma, Yang; McCarty, Samantha; Kapuriya, Naval; Brendel, Victoria; Wang, Chaojie; Zhang, Xiaoli; Jarjoura, David; Saji, Motoyasu; Chen, Ching‐Shih; Ringel, Matthew D.

doi:10.1210/jc.2012-3937

Cited by 26 publications

(17 citation statements)

References 28 publications

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“…Numerous studies showed that phosphorylated p21-activated kinase 1 (PAK1) is involved in cell migration (26)(27)(28)(29). Because PAK1 is considered a key downstream effector of Rac1 signal pathway, we sought to determine the role of PIAS3 in PAK1 activation in RA FLSs.…”

Section: Pias3 Knockdown Decreases Tnf-a-induced Activation Of Pak1 Amentioning

confidence: 99%

Protein Inhibitor of Activated STAT3 Regulates Migration, Invasion, and Activation of Fibroblast-like Synoviocytes in Rheumatoid Arthritis

Lao

Shi

Zou

et al. 2016

The Journal of Immunology

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The aggressive phenotype displayed by fibroblast-like synoviocytes (FLSs) is a critical factor of cartilage destruction in rheumatoid arthritis (RA). Increased FLSs migration and subsequent degradation of the extracellular matrix are essential to the pathology of RA. Protein inhibitor of activated STAT (PIAS), whose family members include PIAS1, PIAS2 (PIASx), PIAS3, and PIAS4 (PIASy), play important roles in regulating various cellular events, such as cell survival, migration, and signal transduction in many cell types. However, whether PIAS proteins have a role in the pathogenesis of RA is unclear. In this study, we evaluated the role of PIAS proteins in FLSs migration, invasion, and matrix metalloproteinases (MMPs) expression in RA. We observed increased expression of PIAS3, but not PIAS1, PIAS2, or PIAS4, in FLSs and synovial tissues from patients with RA. We found that PIAS3 knockdown by short hairpin RNA reduced migration, invasion, and MMP-3, MMP-9, and MMP-13 expression in FLSs. In addition, we demonstrated that PIAS3 regulated lamellipodium formation during cell migration. To gain insight into molecular mechanisms, we evaluated the effect of PIAS3 knockdown on Rac1/PAK1 and JNK activation. Our results indicated that PIAS3-mediated SUMOylation of Rac1 controlled its activation and modulated the Rac1 downstream activity of PAK1 and JNK. Furthermore, inhibition of Rac1, PAK1, or JNK decreased migration and invasion of RA FLSs. Thus, our observations suggest that PIAS3 suppression may be protective against joint destruction in RA by regulating synoviocyte migration, invasion, and activation.

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Section: Pias3 Knockdown Decreases Tnf-a-induced Activation Of Pak1 Amentioning

confidence: 99%

Protein Inhibitor of Activated STAT3 Regulates Migration, Invasion, and Activation of Fibroblast-like Synoviocytes in Rheumatoid Arthritis

Lao

Shi

Zou

et al. 2016

The Journal of Immunology

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“…Currently, recent studies have demonstrated that the inhibition of PAKs might be beneficial in several human conditions such as Neurofibromatosis Type 2 [135,142], fragile X syndrome [136], thyroid cancer [143], other cancers [144,145], and ulcerative colitis [9]. Yet, in spite of the large body of evidence that PAK1/2 regulate NADPH oxidase activity, no PAK inhibitors have been implicated in the regulation of inflammation.…”

Section: Paks As a Pharmacological Targetmentioning

confidence: 99%

P21-activated kinase in inflammatory and cardiovascular disease

Taglieri

Ushio‐Fukai

Monasky

2014

Cellular Signalling

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P-21 activated kinases, or PAKs, are serine–threonine kinases that serve a role in diverse biological functions and organ system diseases. Although PAK signaling has been the focus of many investigations, still our understanding of the role of PAK in inflammation is incomplete. This review consolidates what is known about PAK1 across several cell types, highlighting the role of PAK1 and PAK2 in inflammation in relation to NADPH oxidase activation. This review explores the physiological functions of PAK during inflammation, the role of PAK in several organ diseases with an emphasis on cardiovascular disease, and the PAK signaling pathway, including activators and targets of PAK. Also, we discuss PAK1 as a pharmacological anti-inflammatory target, explore the potentials and the limitations of the current pharmacological tools to regulate PAK1 activity during inflammation, and provide indications for future research. We conclude that a vast amount of evidence supports the idea that PAK is a central molecule in inflammatory signaling, thus making PAK1 itself a promising prospective pharmacological target.

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“…Binding of AR12 is located in the ATP binding pocket of PAK and by using computer modeling AR12 was structurally altered to reduce its PDK1 inhibition and enhance its PAK inhibition. These alterations resulted in a panel of 17 compounds, among them cpd8 (PI-8) and cpd15 (PI-15) (26). Two compounds, cpd4 and cpd15, reduced cell viability and cell migration in thyroid cancer cells, and constitutively active PAK1 rescued the anti-migration effect in thyroid cancer cells indicating that both compounds inhibit PAK activation (26).…”

Section: Introductionmentioning

confidence: 99%

“…These alterations resulted in a panel of 17 compounds, among them cpd8 (PI-8) and cpd15 (PI-15) (26). Two compounds, cpd4 and cpd15, reduced cell viability and cell migration in thyroid cancer cells, and constitutively active PAK1 rescued the anti-migration effect in thyroid cancer cells indicating that both compounds inhibit PAK activation (26). These same studies confirmed that both compounds decreased PAK phosphorylation.…”

Section: Introductionmentioning

confidence: 99%

Inhibiting p21-Activated Kinase Induces Cell Death in Vestibular Schwannoma and Meningioma via Mitotic Catastrophe

Mercado-Pimentel

Miller

Rolph

et al. 2017

Otology &Amp; Neurotology

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Hypothesis p21-Activated Kinase (PAK) regulates signaling pathways that promote cell survival and proliferation; therefore, pharmacological inhibition of PAK will induce cell death in vestibular schwannomas (VS) and meningiomas. Background All VS and many meningiomas result from loss of the neurofibromatosis type 2 (NF2) gene product merlin, with ensuing PAK hyperactivation and increased cell proliferation/survival. Methods The novel small molecule PAK inhibitors PI-8 and PI-15 – tested in schwannoma and meningioma cells – perturb molecular signaling and induce cell death. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), flow cytometry and TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labeling) assay analyzed PAK inhibitors’ effect on cell viability, cell cycle and cell death, respectively. Western blots evaluated activation and expression of cell proliferation, apoptotic, and mitotic catastrophe markers. Light microscopy evaluated cell morphology, and immunocytochemistry analyzed cellular localization of phospho-Merlin and ATG5 (autophagy-related protein). Results Treatment with PI-8 and PI-15 decreased cell viability at 0.65–3.7 μM IC50 in schwannoma and meningioma cells. TUNEL and immunocytochemistry studies show that PI-8 and PI-15 induce mitotic catastrophe but not apoptosis in HEI193 cells while in BenMen1 cells, PI-8 induces autophagy and mitotic catastrophe. PI-15 induces apoptosis in BenMen1 cells. PAK inhibitor treated cells show phospho-Merlin localized to over-duplicated centrosomes of dividing cells, multiple enlarged nuclei, and misaligned/missegregated chromosomes – markers for mitotic catastrophe. Increased ATG5 levels in the nucleus confirmed this cell death type. PI-8 and PI-15 inhibits PAK in both cell lines. However, only PI-15 inhibits AKT (v-Akt Murine Thymoma Viral Oncogene Homolog) in BenMen1 cells. Conclusion PAK inhibitors induce cell death in schwannoma and meningioma cells, at least in part, by mitotic catastrophe.

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Development of p21 Activated Kinase-Targeted Multikinase Inhibitors That Inhibit Thyroid Cancer Cell Migration

Abstract: We have developed 2 new multikinase inhibitors with anti-PAK activity that may serve as scaffolds for further compound development targeting this progression-related thyroid cancer target.

Cited by 26 publications

References 28 publications

Protein Inhibitor of Activated STAT3 Regulates Migration, Invasion, and Activation of Fibroblast-like Synoviocytes in Rheumatoid Arthritis

Protein Inhibitor of Activated STAT3 Regulates Migration, Invasion, and Activation of Fibroblast-like Synoviocytes in Rheumatoid Arthritis

P21-activated kinase in inflammatory and cardiovascular disease

Inhibiting p21-Activated Kinase Induces Cell Death in Vestibular Schwannoma and Meningioma via Mitotic Catastrophe

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