Differential expression and phosphorylation of Pak1 and Pak2 in ovarian cancer: effects on prognosis and cell invasion

Siu, Michelle K.Y.; Wong, Eric T.T.; Chan, Hoi Yan; Kong, Daniel S; Woo, Nina W.S.; Tam, Kwok-kan; Ngan, Hextan Y.S.; Chan, Queeny K.Y.; Chan, Dominic C.W.; Chan, Kelvin Yuen-Kwong; Cheung, Annie N.Y.

doi:10.1002/ijc.25005

Cited by 77 publications

(93 citation statements)

References 43 publications

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“…The oncogenic function of PAK1 is also observed in other cancers, such as colon cancer, neurofibromatosis, and ovarian cancer (31,46,47). Thus, further study targeting PAK1 may provide an optional therapeutic strategy for tumors with PAK1 overexpression.…”

Section: Discussionmentioning

confidence: 97%

Ivermectin Induces Cytostatic Autophagy by Blocking the PAK1/Akt Axis in Breast Cancer

et al. 2016

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Breast cancer is the most common cancer among women worldwide, yet successful treatment remains a clinical challenge. Ivermectin, a broad-spectrum antiparasitic drug, has recently been characterized as a potential anticancer agent due to observed antitumor effects. However, the molecular mechanisms involved remain poorly understood. Here, we report a role for ivermectin in breast cancer suppression by activating cytostatic autophagy both in vitro and in vivo. Mechanistically, ivermectin-induced autophagy in breast cancer cells is associated with decreased P21-activated kinase 1 (PAK1) expression via the ubiquitinationmediated degradation pathway. The inhibition of PAK1 decreases the phosphorylation level of Akt, resulting in the blockade of the Akt/mTOR signaling pathway. In breast cancer xenografts, the ivermectin-induced cytostatic autophagy leads to suppression of tumor growth. Together, our results provide a molecular basis for the use of ivermectin to inhibit the proliferation of breast cancer cells and indicate that ivermectin is a potential option for the treatment of breast cancer. Cancer Res; 76(15); 4457-69. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 97%

Ivermectin Induces Cytostatic Autophagy by Blocking the PAK1/Akt Axis in Breast Cancer

et al. 2016

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“…This finding is intriguing because PAK1 has been observed as the predominant isoform that is frequently activated in ovarian tumors and appears to be associated with tumor aggressiveness (Schraml et al, 2003;Siu et al, 2009). Once activated, PAK1 may locally affect the actin organization through S6K signaling to the actin cytoskeleton CKM Ip et al direct phosphorylation of key signaling targets.…”

Section: S6kmentioning

confidence: 99%

p70 S6 kinase in the control of actin cytoskeleton dynamics and directed migration of ovarian cancer cells

Cheung

Ngan

et al. 2011

Oncogene

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Ovarian cancer is highly metastatic with a poor prognosis. The serine/threonine kinase, p70 S6 kinase (p70 S6K ), which is a downstream effector of phosphatidylinositol 3-kinase/Akt pathway, is frequently activated in ovarian cancer. Here, we show that p70 S6K is a critical regulator of the actin cytoskeleton in the acquisition of the metastatic phenotype. This regulation is through two important activities: p70 S6K acts as an actin filament cross-linking protein and as a Rho family GTPase-activating protein.Ectopic expression of constitutively active p70 S6K in ovarian cancer cells induced a marked reorganization of the actin cytoskeleton and promoted directional cell migration. Using cosedimentation and differential sedimentation assays, p70 S6K was found to directly bind to and cross-link actin filaments. Immunofluorescence studies showed p70S6K colocalized with cytochalasin D-sensitive actin at the leading edge of motile cells. The p70 S6K did not affect the kinetics of spontaneous actin polymerization, but could stabilize actin filaments by the inhibition of cofilin-induced actin depolymerization. In addition, we showed that p70 S6K stimulated the rapid activation of both Rac1 and Cdc42, and their downstream effector p21-activated kinase (PAK1), but not RhoA. Depletion of p70 S6K expression or inhibition of its activity resulted in significant inhibition of actin cytoskeleton reorganization and reduced migration, with a concomitant reduction in Rac1, Cdc42 and PAK1 activation, confirming that the effect was p70 S6K specific. Similarly, the actin cytoskeleton reorganization/migratory phenotype could be reversed by expression of dominant negative Rac1 and Cdc42, or inhibition of PAK1. These results reveal a new direction for understanding the oncogenic roles of p70 S6K in tumor progression.

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“…PAK2 is hyperphosphorylated in ovarian cancer 73 , while an siRNA screen identified GRK6 as required for the viability of myeloma cells but not normal cells 74 . DBF4 is a regulatory subunit of the cell cycle kinase CDC7 and this complex is overexpressed in a variety of cancer cell lines and cancers 75 .…”

Section: Ptmsmentioning

confidence: 99%

Functional proteomics to dissect tyrosine kinase signalling pathways in cancer

2010

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Therefore, it is only by studying the proteome that we can extract functional understanding of the pathways that are deranged in cancer. Rather than just identifying proteins, functional proteomics focuses on the generation of information about proteins, such as expression levels, PTMs and activity, which directly contribute to a functional understanding of the biological system.Functional proteomics feeds directly into the systematic analysis of biochemical networks, often using mathematical modelling or other systems biology tools. It also provides readouts for chemical biology and chemical genetics necessary to interpret the action of drugs.The growing interest in functional proteomics is not only fuelled by the prospect of a true functional understanding, but also by significant improvements in technology and methodology.Advances in mass spectrometry (MS) have extended the sensitivity, accuracy and speed of analysis to now routinely enable the identification of several thousand proteins per experiment. The introduction of MS methods for accurate relative and absolute protein quantification, and the

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Differential expression and phosphorylation of Pak1 and Pak2 in ovarian cancer: effects on prognosis and cell invasion

Cited by 77 publications

References 43 publications

Ivermectin Induces Cytostatic Autophagy by Blocking the PAK1/Akt Axis in Breast Cancer

Ivermectin Induces Cytostatic Autophagy by Blocking the PAK1/Akt Axis in Breast Cancer

p70 S6 kinase in the control of actin cytoskeleton dynamics and directed migration of ovarian cancer cells

Functional proteomics to dissect tyrosine kinase signalling pathways in cancer

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