Interrelationship between protein phosphatase-2A and cytoskeletal architecture during the endothelial cell response to soluble products produced by human head and neck cancer

Tumor neovascularization is necessary for the progressive development of all solid tumors, including head and neck squamous cell carcinomas (HNSCCs). The angiogenic process includes increased endothelial cell motility. Our prior studies have shown the importance of protein phosphatase-2A (PP-2A) in restricting endothelial cell motility. Because motility is regulated by the polymerization/depolymerization of the cellular cytoskeleton, the present study defined the interrelationship between PP-2A and the cytoskeleton during endothelial cell responses to HNSCC-derived angiogenic factors. PP-2A was shown to colocalize with microtubules of unstimulated endothelial cells. However, exposure to HNSCC-derived products resulted in a more diffuse distribution of PP-2A staining and a loss of filamentous tubulin. The feasibility of pharmacologically preventing this cytoskeletal disorganization as a means of blocking tumor-induced angiogenesis was tested. This was accomplished by use of 1α,25-dihydroxyvitamin D3 [1,25 (OH)2D3] and all- trans-retinoic acid to indirectly stimulate PP-2A activity through their capacity to elevated intracellular levels of the second messenger ceramide. Pretreatment of endothelial cells with either 1,25(OH)2D3 or retinoic acid prevented the cytoskeletal disorganization that otherwise occurs in endothelial cells on exposure to HNSCC-derived products. These studies support the feasibility of using elevation of PP-2A to prevent the morphogenic component of the angiogenic process that is stimulated by HNSCC-derived factors.

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Interrelationship between Protein Phosphatase-2A and Cytoskeletal Architecture during the Endothelial Cell Response to Soluble Products Produced by Human Head and Neck Cancer

Otolaryngology ◽

10.1016/s0194-5998(00)70204-x ◽

2000 ◽

Vol 122 (5) ◽

pp. 721-727 ◽

Cited By ~ 7

Author(s):

Christopher J. Witt ◽

Steven P. Gabel ◽

Jeremy Meisinger ◽

Gwendolyn Werra ◽

Shirley W. Liu ◽

...

Keyword(s):

Endothelial Cells ◽

Retinoic Acid ◽

Endothelial Cell ◽

Cell Motility ◽

Head And Neck ◽

Human Head ◽

Dihydroxyvitamin D ◽

Progressive Development ◽

Endothelial Cell Response ◽

Cellular Cytoskeleton

Tumor neovascularization is necessary for the progressive development of all solid tumors, including head and neck squamous cell carcinomas (HNSCCs). The angiogenic process includes increased endothelial cell motility. Our prior studies have shown the importance of protein phos-phatase-2A (PP-2A) in restricting endothelial cell motility. Because motility is regulated by the polymerization/depolymerization of the cellular cytoskeleton, the present study defined the interrelationship between PP-2A and the cytoskeleton during endothelial cell responses to HNSCC-derived angiogenic factors. PP-2A was shown to colocalize with microtubules of unstimulated endothelial cells. However, exposure to HNSCC-derived products resulted in a more diffuse distribution of PP-2A staining and a loss of filamentous tubulin. The feasibility of pharmacologically preventing this cytoskeletal disorganization as a means of blocking tumor-induced angiogenesis was tested. This was accomplished by use of 1α,25-dihydroxyvitamin D3 [1,25 (OH)2D3] and all- trans-retinoic acid to indirectly stimulate PP-2A activity through their capacity to elevated intracellular levels of the second messenger ceramide. Pretreatment of endothelial cells with either 1,25(OH)2D3 or retinoic acid prevented the cytoskeletal disorganization that otherwise occurs in endothelial cells on exposure to HNSCC-derived products. These studies support the feasibility of using elevation of PP-2A to prevent the mor-phogenic component of the angiogenic process that is stimulated by HNSCC-derived factors.

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Protein phosphatase-2A association with microtubules and its role in restricting the invasiveness of human head and neck squamous cell carcinoma cells

Cancer Letters ◽

10.1016/s0304-3835(96)04517-x ◽

1997 ◽

Vol 111 (1-2) ◽

pp. 87-95 ◽

Cited By ~ 17

Author(s):

Jeremy Meisinger ◽

Snehal Patel ◽

Kishore Vellody ◽

Richard Bergstrom ◽

Janet Benefield ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Protein Phosphatase ◽

Protein Phosphatase 2A ◽

Human Head ◽

Carcinoma Cells ◽

Neck Squamous Cell Carcinoma ◽

Phosphatase 2A

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Protein phosphatase-2A regulates endothelial cell motility and both the phosphorylation and the stability of focal adhesion complexes

International Journal of Cancer ◽

10.1002/ijc.10491 ◽

2002 ◽

Vol 100 (3) ◽

pp. 276-282 ◽

Cited By ~ 29

Author(s):

M. Rita I. Young ◽

Kristin Kolesiak ◽

Jeremy Meisinger

Keyword(s):

Endothelial Cell ◽

Cell Motility ◽

Focal Adhesion ◽

Protein Phosphatase ◽

Protein Phosphatase 2A ◽

Phosphatase 2A ◽

The Stability

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Tumor-derived prostaglandin E2 and transforming growth factor-? stimulate endothelial cell motility through inhibition of protein phosphatase-2A and involvement of PTEN and phosphatidy linositide 3-kinase

Angiogenesis ◽

10.1007/s10456-004-1027-2 ◽

2004 ◽

Vol 7 (2) ◽

pp. 123-131 ◽

Cited By ~ 9

Author(s):

M. Rita I. Young

Keyword(s):

Endothelial Cell ◽

Growth Factor ◽

Prostaglandin E2 ◽

Cell Motility ◽

Protein Phosphatase ◽

Transforming Growth Factor ◽

Protein Phosphatase 2A ◽

Phosphatase 2A

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Troglitazone acutely inhibits protein synthesis in endothelial cells via a novel mechanism involving protein phosphatase 2A-dependent p70 S6 kinase inhibition

AJP Cell Physiology ◽

10.1152/ajpcell.00491.2005 ◽

2006 ◽

Vol 291 (2) ◽

pp. C317-C326 ◽

Cited By ~ 36

Author(s):

Du-Hyong Cho ◽

Yoon Jung Choi ◽

Sangmee Ahn Jo ◽

Jungsang Ryou ◽

Jin Yi Kim ◽

...

Keyword(s):

Endothelial Cells ◽

Protein Synthesis ◽

Protein Phosphatase ◽

Protein Phosphatase 2A ◽

Peroxisome Proliferator ◽

Inhibitory Effects ◽

S6 Kinase ◽

P70 S6 Kinase ◽

Inhibition Of Protein Synthesis ◽

Phosphatase 2A

Thiazolidinediones (TZDs), synthetic peroxisome proliferator-activated receptor γ (PPARγ) ligands, have been implicated in the inhibition of protein synthesis in a variety of cells, but the underlying mechanisms remain obscure. We report that troglitazone, the first TZD drug, acutely inhibited protein synthesis by decreasing p70 S6 kinase (p70S6K) activity in bovine aortic endothelial cells (BAEC). This inhibition was not accompanied by decreased phosphorylation status or in vitro kinase activity of mammalian target of rapamycin (mTOR). Furthermore, cotreatment with rapamycin, a specific mTOR inhibitor, and troglitazone additively inhibited both p70S6K activity and protein synthesis, suggesting that the inhibitory effects of troglitazone are not mediated by mTOR. Overexpression of the wild-type p70S6K gene significantly reversed the troglitazone-induced inhibition of protein synthesis, indicating an important role of p70S6K. Okadaic acid, a protein phosphatase 2A (PP2A) inhibitor, partially reversed the troglitazone-induced inhibition of p70S6K activity and protein synthesis. Although troglitazone did not alter total cellular PP2A activity, it increased the physical association between p70S6K and PP2A, suggesting an underlying molecular mechanism. GW9662, a PPARγ antagonist, did not alter any of the observed inhibitory effects. Finally, we also found that the mTOR-independent inhibitory mechanism of troglitazone holds for the TZDs ciglitazone, pioglitazone, and rosiglitazone, in BAEC and other types of endothelial cells tested. In conclusion, our data demonstrate for the first time that troglitazone (and perhaps other TZDs) acutely decreases p70S6K activity through a PP2A-dependent mechanism that is independent of mTOR and PPARγ, leading to the inhibition of protein synthesis in endothelial cells.

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