Clinical Evaluation of P21 Activated Kinase 1 (PAK1) Activation in Gliomas and Its Effect on Cell Proliferation

Venu, Akkanapally; Archana, B; Kanumuri, Rahul; Vuttaradhi, Veena K.; D’Cruze, Lawrence; Murugan, Sowmiya; Krishnamurthy, Ganga; Prathiba, D; Alexandrovna, Dymova Mayya; Kumar, R. Suresh; Venkatraman, Ganesh

doi:10.1080/07357907.2020.1858097

Cited by 11 publications

(9 citation statements)

References 48 publications

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“…However, if and how the nuclear and cytoplasmic localizations of the different PAK isoforms link to overall survival and therapy response is only beginning to emerge. Earlier studies identified an association between high PAK1 expression, in general, particularly of phosphorylated cytoplasmic PAK1, and poor prognoses in glioblastoma patients [ 27 , 28 ]. In contrast, nuclear PAK1 binds to chromatin and may be involved in gene transcription [ 42 , 44 ] and DNA damage response [ 51 , 52 ].…”

Section: Discussionmentioning

confidence: 99%

“…Studies in various cancer entities underline that PAKs can function as drivers of epithelial-to-mesenchymal transition (EMT), cancer growth, and resistance to chemotherapy or small molecule inhibitors [ 20 , 24 , 25 , 26 ]. In glioblastoma, PAK1 phosphorylation in the cytoplasm and its expression level correlate with patient prognosis [ 27 , 28 ]. Furthermore, the inhibition of PAK5 reduces glioblastoma cell tumorigenicity [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

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Targeting of p21-Activated Kinase 4 Radiosensitizes Glioblastoma Cells via Impaired DNA Repair

Blankenstein

Cordes

Kunz-Schughart

et al. 2022

Cells

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Glioblastoma is a devastating malignant disease with poor patient overall survival. Strong invasiveness and resistance to radiochemotherapy have challenged the identification of molecular targets that can finally improve treatment outcomes. This study evaluates the influence of all six known p21-activated kinase (PAK) protein family members on the invasion capacity and radio-response of glioblastoma cells by employing a siRNA-based screen. In a panel of human glioblastoma cell models, we identified PAK4 as the main PAK isoform regulating invasion and clonogenic survival upon irradiation and demonstrated the radiosensitizing potential of PAK4 inhibition. Mechanistically, we show that PAK4 depletion and pharmacological inhibition enhanced the number of irradiation-induced DNA double-strand breaks and reduced the expression levels of various DNA repair proteins. In conclusion, our data suggest PAK4 as a putative target for radiosensitization and impairing DNA repair in glioblastoma, deserving further scrutiny in extended combinatorial treatment testing.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targeting of p21-Activated Kinase 4 Radiosensitizes Glioblastoma Cells via Impaired DNA Repair

Blankenstein

Cordes

Kunz-Schughart

et al. 2022

Cells

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“…The (GEF) Asef2 has been shown to increase RAC and CDC42 expression, resulting in enhanced cancer cell migration and metastasis ( 41 ). The essential downstream regulator of RAC1 and CDC42 is PAK, which plays vital roles in cancer initiation, growth, angiogenesis, immunity, metabolism, metastasis, and drug resistance ( 42 – 44 ). Upregulation of PAK expression by RAC/CDC42 induces the formation of lamellipodia, filopodia, membrane folds, and stress fibers, and the remodeling of focal adhesion complexes ( 45 ).…”

Section: Discussionmentioning

confidence: 99%

Potential Resistance to Antineoplastic Aminated Fullerenes Mediated by M2-Like Monocyte-Derived Exosomes

et al. 2022

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Exosomes are small extracellular vesicles critical for intercellular signaling via their delivery of cargoes, including proteins, DNA, RNA, lipids, and metabolites. Exosomes play essential roles in remodeling the tumor microenvironment (TME) for tumor growth, metastasis, and drug resistance. Aminated fullerenes (e.g., C70-ethylenediamine [EDA]) exhibit antineoplastic effects by targeting multiple functional proteins. Nanosized C70-EDA with positive surface charges tends to be taken up by monocytes in the bloodstream and monocyte-derived macrophages in the TME. Herein, the alterations of monocytes and monocyte-derived exosomes by C70-EDA have been investigated. C70-EDA reprogramed THP-1 monocyte to an M2-like state and substantially increased the protein content in exosomes secreted by M2-like monocytes. Notably, C70-EDA-induced M2-like monocytes released exosomes that triggered the proliferation of recipient tumor cells, which may alleviate the antineoplastic efficacy of C70-EDA. As revealed by proteomic profiling of exosomes, this outcome is probably a result of Rho GTPase/p21-activated kinase (PAK) pathway activation in recipient tumor cells induced by upregulated exosomal proteins. This work indicates a promising strategy in which aminated fullerenes can be combined with PAK inhibitors for cancer therapy.

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“…Cancer is one of the major health burdens worldwide. PAKs have been proved to be pivotal in cancer initiation, growth, angiogenesis, immunity, metabolism, metastasis, and drug resistance (Akkanapally et al, 2020;Bautista et al, 2020;Huang et al, 2020). PAKs may, through several signaling pathways, regulate cancer cell growth, apoptosis, or autophagy.…”

Section: P21-activated Kinases In Cancermentioning

confidence: 99%

The Role of p21-Activated Kinases in Cancer and Beyond: Where Are We Heading?

Liu

Dong

2021

Front. Cell Dev. Biol.

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The p21-activated kinases (PAKs), downstream effectors of Ras-related Rho GTPase Cdc42 and Rac, are serine/threonine kinases. Biologically, PAKs participate in various cellular processes, including growth, apoptosis, mitosis, immune response, motility, inflammation, and gene expression, making PAKs the nexus of several pathogenic and oncogenic signaling pathways. PAKs were proved to play critical roles in human diseases, including cancer, infectious diseases, neurological disorders, diabetes, pancreatic acinar diseases, and cardiac disorders. In this review, we systematically discuss the structure, function, alteration, and molecular mechanisms of PAKs that are involved in the pathogenic and oncogenic effects, as well as PAK inhibitors, which may be developed and deployed in cancer therapy, anti-viral infection, and other diseases. Furthermore, we highlight the critical questions of PAKs in future research, which provide an opportunity to offer input and guidance on new directions for PAKs in pathogenic, oncogenic, and drug discovery research.

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Clinical Evaluation of P21 Activated Kinase 1 (PAK1) Activation in Gliomas and Its Effect on Cell Proliferation

Cited by 11 publications

References 48 publications

Targeting of p21-Activated Kinase 4 Radiosensitizes Glioblastoma Cells via Impaired DNA Repair

Targeting of p21-Activated Kinase 4 Radiosensitizes Glioblastoma Cells via Impaired DNA Repair

Potential Resistance to Antineoplastic Aminated Fullerenes Mediated by M2-Like Monocyte-Derived Exosomes

The Role of p21-Activated Kinases in Cancer and Beyond: Where Are We Heading?

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