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, Anna; Al-Azayzih, Ahmad; Abdalla, Maha; Al‐Husein, Belal; Kavuri, Sravankumar; Lee, Jeffrey; Moses, Kelvin A.; Somanath, Payaningal R.

doi:10.1074/jbc.m112.424770

Cited by 74 publications

(78 citation statements)

References 28 publications

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“…Electric cell-substrate impedance sensing (ECIS) assay for cancer cell microinvasion: Cancer cell transendothelial migration (microinvasion) was studied using the ability of cancer cells to penetrate the endothelial monolayer and thus disrupt the endothelial-barrier integrity (measured as electrical resistance of the endothelial monolayer) as determined using Electric Cell-substrate Impedance Sensing (ECIS) technology from Applied Biophysics (Troy, NY) [33, 53]. Briefly, HMEC were seeded in 1:1 density on gelatin-coated ECIS arrays (8W10E+), each containing 8 wells with 16 gold electrodes per well.…”

Section: Methodsmentioning

confidence: 99%

Discrete functions of GSK3α and GSK3β isoforms in prostate tumor growth and micrometastasis

2015

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Isoform specific function of glycogen synthase kinase-3 (GSK3) in cancer is not well defined. We report that silencing of GSK3α, but not GSK3β expression inhibited proliferation, survival and colony formation by the PC3, DU145 and LNCaP prostate cancer cells, and the growth of PC3 tumor xenografts in athymic nude mice. Silencing of GSK3α, but not GSK3β resulted in reduced proliferation and enhanced apoptosis in tumor xenografts. ShRNA-mediated knockdown of GSK3α and GSK3β equally inhibited the ability of prostate cancer cells to migrate and invade the endothelial-barrier in vitro, and PC3 cell micrometastasis to lungs in vivo. Mechanistically, whereas silencing GSK3α resulted in increased expression of pro-apoptotic markers cleaved caspase-3 and cleaved caspase-9 in LNCaP, PC3 and DU145 cells, silencing GSK3β resulted in the inhibition of cell scattering, establishment of cell-cell contacts, increased expression and membrane localization of β-catenin, and reduced expression of epithelial to mesenchymal transition (EMT) markers such as Snail and MMP-9. This indicated the specific role of GSK3β in EMT, acquisition of motility and invasive potential. Overall, our data demonstrated the isoform specific role of GSK3α and GSK3β in prostate cancer cells in vitro, and tumor growth and micrometastasis in vivo, via distinct molecular and cellular mechanisms.

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Section: Methodsmentioning

confidence: 99%

Discrete functions of GSK3α and GSK3β isoforms in prostate tumor growth and micrometastasis

2015

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“…ECIS assay was performed as previously described [21, 22]. Briefly, 8-well chamber arrays covered which gold plated electrodes were filled with 400 μl of electrode-stabilizing solution and incubated for 30 minutes.…”

Section: Methodsmentioning

confidence: 99%

TNFα induces inflammatory stress response in microvascular endothelial cells via Akt- and P38 MAP kinase-mediated thrombospondin-1 expression

et al. 2015

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Tumor necrosis factor-α (TNFα) and thrombospondin-1 (TSP-1) are well-known mediators of inflammation. However, a causal relationship between TNFα stimuli and TSP-1 expression in endothelial cell stress, and the underlying mechanisms has not yet been investigated. In our study, human microvascular endothelial cells (hMEC) were treated with TNFα and analyzed for endothelial dysfunction, TSP-1 expression and associated mechanisms. TNFα treatment induced a dose-dependent increase in TSP-1 expression in hMEC associated with increased endothelial permeability, apoptosis and reduced proliferation. Whereas TNFα activated Akt, ERK and P38 MAPK simultaneously in hMEC, inhibitors of Akt and P38 MAPK, but not ERK blunted TNFα-induced TSP-1 expression. Silencing of NFκB gene had no significant effect on TNFα-induced TSP-1 expression. Our study demonstrates the novel role of TNFα in inducing inflammatory stress response in hMEC through Akt- and P38 MAPK-mediated expression of TSP-1, independent of NFκB signaling.

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“…The protein concentration was measured by the D L protein assay (Bio-Rad). Western blot analyses were performed as described previously (Goc et al, 2013).…”

Section: Methodsmentioning

confidence: 99%

Clinically Relevant Doses of Candesartan Inhibit Growth of Prostate Tumor Xenografts In Vivo through Modulation of Tumor Angiogenesis

Alhusban

Al-Azayzih

Goc

et al. 2014

J Pharmacol Exp Ther

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Angiotensin II receptor type 1 blockers (ARBs), widely used antihypertensive drugs, have also been investigated for their anticancer effects. The effect of ARBs on prostate cancer in experimental models compared with meta-analysis data from clinical trials is conflicting. Whereas this discrepancy might be due to the use of supratherapeutic doses of ARBs in cellular and animal models as compared with the clinical doses used in human trials, further investigation of the effects of clinical doses of ARBs on prostate cancer in experimental models is warranted. In the current study, we sought to determine the effects of candesartan on prostate cancer cellular function in vitro and tumor growth in vivo, and characterize the underlying mechanisms. Our analysis indicated that clinically relevant doses of candesartan significantly inhibited growth of PC3 cell tumor xenografts in mice.Interestingly, the same concentrations of candesartan actually promoted prostate cancer cellular function in vitro, through a modest but significant inhibition in apoptosis. Inhibition of tumor growth by candesartan was associated with a decrease in vascular endothelial growth factor (VEGF) expression in tumors and inhibition of tumor angiogenesis, but normalization of tumor vasculature. Although candesartan did not impair PC3 cell viability, it inhibited endothelialbarrier disruption by tumor-derived factors. Furthermore, candesartan significantly inhibited expression of VEGF in PC3 and DU145 cell lines independent of angiotensin II type 2 receptor, but potentially via angiotensin II type 1 receptor inhibition. Our findings clearly demonstrate the therapeutic potential of candesartan for prostate cancer and establish a link between ARBs, VEGF expression, and prostate tumor angiogenesis.

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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

Cited by 74 publications

References 28 publications

Discrete functions of GSK3α and GSK3β isoforms in prostate tumor growth and micrometastasis

Discrete functions of GSK3α and GSK3β isoforms in prostate tumor growth and micrometastasis

TNFα induces inflammatory stress response in microvascular endothelial cells via Akt- and P38 MAP kinase-mediated thrombospondin-1 expression

Clinically Relevant Doses of Candesartan Inhibit Growth of Prostate Tumor Xenografts In Vivo through Modulation of Tumor Angiogenesis

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