Inhibition of p21-activated Kinase 6 (PAK6) Increases Radiosensitivity of Prostate Cancer Cells

Zhang, M.; Siedow, Michael; Saia, Gregory; Palannichamy, K.; Lautenschlaeger, Tim; Chakravarti, Arnab

doi:10.1016/j.ijrobp.2008.06.815

Cited by 10 publications

(12 citation statements)

References 30 publications

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“…As reported in the literature (9,22), our data confirmed that prostate cancer cells express a robust amount of Pak6 irrespective of their tumorigenic and metastatic potential. Although protein expression levels of Pak1 were relatively less in noninvasive LNCaP cells, expression of Pak1 in highly invasive prostate cancer cells such as PC3, LNCaP C4-2, and Vertebral Cancer of the Prostate (VCaP) were significantly higher compared with less aggressive LNCaP cells, thus suggesting the pre- dominant role of Pak1 in prostate cancer cell invasion and metastasis.…”

Section: Discussionsupporting

confidence: 90%

P21 Activated Kinase-1 (Pak1) Promotes Prostate Tumor Growth and Microinvasion via Inhibition of Transforming Growth Factor β Expression and Enhanced Matrix Metalloproteinase 9 Secretion

Goc

Al-Azayzih

Abdalla

et al. 2013

Journal of Biological Chemistry

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Background:The significance of Pak1 in prostate cancer remains unclear. Results: Pak1 knockdown impaired prostate tumor growth via increased expression of TGF␤ and reduced secretion of MMP9. Conclusions:We demonstrated that Pak1 is a more potent mediator of prostate cancer cell migration and tumor growth than Pak6, the predominant isoform in the prostate. Significance: A novel role of Pak1 in prostate cancer is identified.

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Section: Discussionsupporting

confidence: 90%

P21 Activated Kinase-1 (Pak1) Promotes Prostate Tumor Growth and Microinvasion via Inhibition of Transforming Growth Factor β Expression and Enhanced Matrix Metalloproteinase 9 Secretion

Goc

Al-Azayzih

Abdalla

et al. 2013

Journal of Biological Chemistry

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“…PAK6, an oncogene belonging to the group II of the p21 activated kinase family (PAK), has been shown to be expressed at low levels in normal adult tissues, whereas it is over‐expressed in HepG2 liver cancer cells and represents a marker for poor prognosis in HCC . PAK6 knockdown in prostate cancer cell lines showed less proliferation, more apoptosis and more DNA double‐strand breaks after radiation with six Gy . Here, we could show that panobinostat treatment of HCC cell lines Hep3B and HepG2 led to a significant downregulation of PAK6.…”

Section: Discussionmentioning

confidence: 84%

The pan‐deacetylase inhibitor panobinostat suppresses the expression of oncogenic miRNAs in hepatocellular carcinoma cell lines

Henrici

Montalbano

Neureiter

et al. 2013

Molecular Carcinogenesis

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Deacetylase inhibitors (DACi) are a new class of drugs with a broad spectrum of mechanisms that favor their application in cancer therapy. Currently, the exact mechanisms and cellular effects of DACi have not been fully elucidated. In addition to their effects on histone acetylation, DACi can interfere with gene expression via miRNA pathways. Treatment with panobinostat (LBH589), a novel potent DACi, led to the highly aberrant modulation of several miRNAs in hepatocellular carcinoma (HCC) cell lines as shown by miRNA array analysis. Among them, hsa-miR-19a, hsa-miR-19b1 and the corresponding precursors were down-regulated by panobinostat in TP53(-/-) Hep3B and TP53(+/+) HepG2 cell lines; hsa-miR30a-5p mature form only was suppressed in both HCC cell lines, as confirmed by further RT-qPCR analysis. In HCC cell lines, panobinostat caused the upregulation of the predicted miRNA targets APAF1 and Beclin1 protein levels. Transfection with oligonucleotides mimicking these miRNAs led to an increase in the viability rate of both cell lines as analyzed by impedance-based real-time cell analysis. In addition, transfecting miRNA mimicking oligonucleotides resulted in the decrease of APAF1, Beclin1 and PAK6 at the protein level, proving the regulating influence of the investigated miRNAs on gene final products. The overexpression of the above mentioned oncomiRs in Hep3B and HepG2 cell lines leads to cell proliferation and downregulation of cell death associated proteins. In our model, panobinostat exerts its anti-cancer effect by suppressing these miRNAs and restoring the expression of their corresponding tumor suppressor targets.

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“…Using lentiviral infection, we generated stable DU145 prostate cancer cell lines expressing GFP or GFP-PAK6. DU145 prostate cancer cells were chosen because they are known to express endogenous PAK6 (Wen et al, 2009;Zhang et al, 2010) and because they have previously been used to investigate PAK6 localization (Fram et al, 2014). Using these cells we found that GFP-PAK6 localizes to cell-cell adhesions as defined by E-cadherin and F-actin staining, whereas the control GFP construct does not (Fig.…”

Section: Pak6 Targets To Cell-cell Adhesionsmentioning

confidence: 98%

PAK6 targets to cell-cell adhesions via its N-terminus in a Cdc42-dependent manner to drive epithelial colony escape

Morse

Sun

Olberding

et al. 2015

Journal of Cell Science

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The six serine/threonine kinases in the p21-activated kinase (PAK) family are important regulators of cell adhesion, motility and survival. PAK6, which is overexpressed in prostate cancer, was recently reported to localize to cell-cell adhesions and to drive epithelial cell colony escape. Here we report that PAK6 targeting to cell-cell adhesions occurs through its N-terminus, requiring both its Cdc42/ Rac interactive binding (CRIB) domain and an adjacent polybasic region for maximal targeting efficiency. We find PAK6 localization to cell-cell adhesions is Cdc42-dependent, as Cdc42 knockdown inhibits PAK6 targeting to cell-cell adhesions. We further find the ability of PAK6 to drive epithelial cell colony escape requires kinase activity and is disrupted by mutations that perturb PAK6 cell-cell adhesion targeting. Finally, we demonstrate that all type II PAKs (PAK4, PAK5 and PAK6) target to cell-cell adhesions, albeit to differing extents, but PAK1 (a type I PAK) does not. Notably, the ability of a PAK isoform to drive epithelial colony escape correlates with its targeting to cell-cell adhesions. We conclude that PAKs have a broader role in the regulation of cell-cell adhesions than previously appreciated.

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Inhibition of p21-activated Kinase 6 (PAK6) Increases Radiosensitivity of Prostate Cancer Cells

Cited by 10 publications

References 30 publications

P21 Activated Kinase-1 (Pak1) Promotes Prostate Tumor Growth and Microinvasion via Inhibition of Transforming Growth Factor β Expression and Enhanced Matrix Metalloproteinase 9 Secretion

P21 Activated Kinase-1 (Pak1) Promotes Prostate Tumor Growth and Microinvasion via Inhibition of Transforming Growth Factor β Expression and Enhanced Matrix Metalloproteinase 9 Secretion

The pan‐deacetylase inhibitor panobinostat suppresses the expression of oncogenic miRNAs in hepatocellular carcinoma cell lines

PAK6 targets to cell-cell adhesions via its N-terminus in a Cdc42-dependent manner to drive epithelial colony escape

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