Thiolutin inhibits endothelial cell adhesion by perturbing Hsp27 interactions with components of the actin and intermediate filament cytoskeleton

Jia, Yan; Wu, Shiaw‐Lin; Isenberg, Jeff S.; Dai, Shujia; Sipes, John M.; Field, Lyndsay; Zeng, Bixi; Bandle, Russell W.; Ridnour, Lisa A.; Wink, David A.; Ramchandran, Ramani; Karger, Barry L.; Roberts, D. A.

doi:10.1007/s12192-009-0130-0

Cited by 37 publications

(33 citation statements)

References 61 publications

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“…Also, our results support a recent model proposed by Doshi et al (2009) relating the stability of the actin cytoskeleton to HSP27 in the regulation of movement in heat shocked human cancer cells. This latter study is supported by the studies of Jia et al (2009) examining the effect of thiolutin, an organosulfur compound, on cytoskeletal structure and cell adhesion of zebrafish endothelial cells.…”

Section: Discussionmentioning

confidence: 71%

Proteasome inhibition induces hsp30 and hsp70 gene expression as well as the acquisition of thermotolerance in Xenopus laevis A6 cells

Young

Heikkila

2010

Cell Stress and Chaperones

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Previous studies have shown that inhibiting the activity of the proteasome leads to the accumulation of damaged or unfolded proteins within the cell. In this study, we report that proteasome inhibitors, lactacystin and carbobenzoxy-L-leucyl-L-leucyl-L-leucinal (MG132), induced the accumulation of ubiquitinated proteins as well as a dose-and time-dependent increase in the relative levels of heat shock protein (HSP)30 and HSP70 and their respective mRNAs in Xenopus laevis A6 kidney epithelial cells. In A6 cells recovering from MG132 exposure, HSP30 and HSP70 levels were still elevated after 24 h but decreased substantially after 48 h. The activation of heat shock factor 1 (HSF1) may be involved in MG132-induced hsp gene expression in A6 cells since KNK437, a HSF1 inhibitor, repressed the accumulation of HSP30 and HSP70. Exposing A6 cells to simultaneous MG132 and mild heat shock enhanced the accumulation of HSP30 and HSP70 to a much greater extent than with each stressor alone. Immunocytochemical studies determined that HSP30 was localized primarily in the cytoplasm of lactacystin-or MG132-treated cells. In some cells treated with higher concentrations of MG132 or lactacystin, we observed in the cortical cytoplasm (1) relatively large HSP30 staining structures, (2) colocalization of actin and HSP30, and (3) cytoplasmic areas that were devoid of HSP30. Lastly, MG132 treatment of A6 cells conferred a state of thermotolerance such that they were able to survive a subsequent thermal challenge.

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Section: Discussionmentioning

confidence: 71%

Proteasome inhibition induces hsp30 and hsp70 gene expression as well as the acquisition of thermotolerance in Xenopus laevis A6 cells

Young

Heikkila

2010

Cell Stress and Chaperones

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“…Interestingly, phosphorylation of vimentin, which decelerates intermediate filament formation during epithelial-mesenchymal transition (40; (Fig. 5D) and phosphorylation of HSPb1, which mediates its antiadhesive activity through cytoskeleton dynamic control (41), were increased after Lith-O-Asp treatment (Table 1). Our 2DE-MS/MS and IP-Western results confirmed that a-2,3-ST isotype, ST3Gal IV, was phosphorylated after Lith-O-Asp treatment (Table 1 and Fig.…”

Section: Discussionmentioning

confidence: 99%

A Novel Sialyltransferase Inhibitor Suppresses FAK/Paxillin Signaling and Cancer Angiogenesis and Metastasis Pathways

et al. 2011

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Increased sialyltransferase (ST) activity promotes cancer cell metastasis, and overexpression of cell surface sialic acid correlates with poor prognosis in cancer patients. To seek therapies targeting metastasis for cancer treatment, we developed a novel ST inhibitor, Lith-O-Asp, and investigated its antimetastatic and antiangiogenic effects and mechanisms. We found that cells treated with Lith-O-Asp showed a reduction of activity on various ST enzymes by in vitro and cell-based activity analyses. Lith-O-Asp inhibited migration and invasion abilities in various cancer cell lines and showed inhibitory effect on the angiogenic activity of human umbilical vein endothelial cells. Indeed, Lith-O-Asp treatment consequently delayed cancer cell metastasis in experimental and spontaneous metastasis assays in animal models. Importantly, Lith-O-Asp decreased the sialic acid modification of integrin-b1 and inhibited the expression of phospho-FAK, phospho-paxillin, and the matrix metalloprotease

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“…In vitro, HSP27 was proposed to sequester actin monomers and weakly cap F-actin in a phosphorylation-dependent manner During et al 2007;Doshi et al 2010;Jia et al 2010). This suggested that IGF2BP1 could control actin dynamics by antagonizing MK5-directed phosphorylation of HSP27.…”

Section: Igf2bp1 Controls Actin Dynamics By Antagonizing the Phosphormentioning

confidence: 99%

IGF2BP1 promotes cell migration by regulating MK5 and PTEN signaling

et al. 2012

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In primary neurons, the oncofetal RNA-binding protein IGF2BP1 (IGF2 mRNA-binding protein 1) controls spatially restricted b-actin (ACTB) mRNA translation and modulates growth cone guidance. In cultured tumorderived cells, IGF2BP1 was shown to regulate the formation of lamellipodia and invadopodia. However, how and via which target mRNAs IGF2BP1 controls the motility of tumor-derived cells has remained elusive. In this study, we reveal that IGF2BP1 promotes the velocity and directionality of tumor-derived cell migration by determining the cytoplasmic fate of two novel target mRNAs: MAPK4 and PTEN. Inhibition of MAPK4 mRNA translation by IGF2BP1 antagonizes MK5 activation and prevents phosphorylation of HSP27, which sequesters actin monomers available for F-actin polymerization. Consequently, HSP27-ACTB association is reduced, mobilizing cellular G-actin for polymerization in order to promote the velocity of cell migration. At the same time, stabilization of the PTEN mRNA by IGF2BP1 enhances PTEN expression and antagonizes PIP 3 -directed signaling. This enforces the directionality of cell migration in a RAC1-dependent manner by preventing additional lamellipodia from forming and sustaining cell polarization intrinsically. IGF2BP1 thus promotes the velocity and persistence of tumor cell migration by controlling the expression of signaling proteins. This fine-tunes and connects intracellular signaling networks in order to enhance actin dynamics and cell polarization.

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Thiolutin inhibits endothelial cell adhesion by perturbing Hsp27 interactions with components of the actin and intermediate filament cytoskeleton

Abstract: Thiolutin is a dithiole synthesized by Streptomyces sp. that inhibits endothelial cell adhesion and tumor growth. We show here that thiolutin potently inhibits developmental angiogenesis in zebrafish and vascular outgrowth from tissue explants in 3D cultures.

Cited by 37 publications

References 61 publications

Proteasome inhibition induces hsp30 and hsp70 gene expression as well as the acquisition of thermotolerance in Xenopus laevis A6 cells

Proteasome inhibition induces hsp30 and hsp70 gene expression as well as the acquisition of thermotolerance in Xenopus laevis A6 cells

A Novel Sialyltransferase Inhibitor Suppresses FAK/Paxillin Signaling and Cancer Angiogenesis and Metastasis Pathways

IGF2BP1 promotes cell migration by regulating MK5 and PTEN signaling

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