Thymosin  4 has tumor suppressive effects and its decreased expression results in poor prognosis and decreased survival in multiple myeloma

Caers, Jo; Hose, Dirk; Kuipers, Ine; Bos, Tomas; Valckenborgh, Els Van; Menu, Eline; Bruyne, Elke De; Goldschmidt, Hartmut; Camp, Ben Van; Klein, Bernard; Vanderkerken, Karin

doi:10.3324/haematol.2009.006411

Cited by 21 publications

(26 citation statements)

References 26 publications

(19 reference statements)

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“…In fact, the isolation of Dictyostelium Abns, SepA, TNLA/B, and DSPA has already suggested that this may be the case. Thymosin β4, a human member of the Actobindin family, has been reported to play the role of both an oncogene and tumor suppressor under different contexts (82,83). SepA shares homology with human MSTs and PAKs, known tumor supressors that are currently being investigated as therapeutic targets (84,85).…”

Section: Regulators Of Adhesion and Motility Reveal Multiple Points Ofmentioning

confidence: 99%

Shear force-based genetic screen reveals negative regulators of cell adhesion and protrusive activity

Lampert

Kamprad

Edwards

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The model organism Dictyostelium discoideum has greatly facilitated our understanding of the signal transduction and cytoskeletal pathways that govern cell motility. Cell-substrate adhesion is downstream of many migratory and chemotaxis signaling events. Dictyostelium cells lacking the tumor suppressor PTEN show strongly impaired migratory activity and adhere strongly to their substrates. We reasoned that other regulators of migration could be obtained through a screen for overly adhesive mutants. A screen of restriction enzyme-mediated integration mutagenized cells yielded numerous mutants with the desired phenotypes, and the insertion sites in 18 of the strains were mapped. These regulators of adhesion and motility mutants have increased adhesion and decreased motility. Characterization of seven strains demonstrated decreased directed migration, flatness, increased filamentous actin-based protrusions, and increased signal transduction network activity. Many of the genes share homology to human genes and demonstrate the diverse array of cellular networks that function in adhesion and migration

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Section: Regulators Of Adhesion and Motility Reveal Multiple Points Ofmentioning

confidence: 99%

Shear force-based genetic screen reveals negative regulators of cell adhesion and protrusive activity

Lampert

Kamprad

Edwards

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…daily vs bi-weekly) at a higher dosage could not only block but also reverse the pathologic process. However, considering the potential role of Ac-SDKP in some malignancies [26–29], even though controversial [30], caution should be used to determine whether Ac-SDKP can be harmful in a subset of patients. Nevertheless we must seriously consider the potential therapeutic utilization of Ac-SDKP against pulmonary fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Preventive and therapeutic effects of thymosin β4 N-terminal fragment Ac-SDKP in the bleomycin model of pulmonary fibrosis

et al. 2016

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In this study, the bleomycin model of pulmonary fibrosis was utilized to investigate putative anti-fibrotic activity of Ac-SDKP in vivo. Male CD-1 mice received intra-tracheal bleomycin (BLEO, 1 mg/kg) instillation in the absence or presence of Ac-SDKP (a dose of 0.6 mg/kg delivered intra-peritoneally on the day of BLEO treatment, d0, followed by bi-weekly additional doses). To evaluate therapeutic effects in a subset of mice, Ac-SDKP was administered one week after BLEO instillation (d7). Animals were sacrificed at one, two, or three weeks later. Measurement of fluid and collagen content in the lung, Broncho Alveolar Lavage Fluid (BALF) analysis, lung histology, immunohistochemistry (IHC), and molecular analysis were performed. Compared to BLEO-treated mice, animals that received also Ac-SDKP (at both d0 and d7) had significantly decreased mortality, weight loss, inflammation (edema, and leukocyte lung infiltration), lung damage (histological evidence of lung injury), and fibrosis (collagen histological staining and soluble collagen content in the lung) at up to 21 days. Moreover, IHC and quantitative RT-PCR results demonstrated a significant decrease in BLEO-induced IL-17 and TGF-β expression in lung tissue. Importantly, α-SMA expression, the hallmark of myofibroblast differentiation, was also decreased. This is the first report showing not only a preventive protective role of Ac-SDKP but also its significant therapeutic effects in the bleomycin model of pulmonary fibrosis, thus supporting further preclinical and clinical studies.

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“…While some studies have suggested that Tβ4 has a role in metastasis (Wang et al., 2004) (Xiao et al., 2012), Caers et al. have shown a tumor suppressive function of Tβ4 in myeloma development (Caers et al., 2010a). Tβ4 is a poor prognostic factor in a number of different types of tumors and a good prognostic indicator in multiple myeloma (Caers et al., 2010a; Xiao et al., 2012; Caers et al., 2010b).…”

Section: Discussionmentioning

confidence: 99%

Thymosin‐β4 is a determinant of drug sensitivity for Fenretinide and Vorinostat combination therapy in neuroblastoma

et al. 2015

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Keywords:Thymosin-b4 (Tb4) 4-HPR SAHA NeuroblastomaHistone deacetylase inhibitors and retinoic acid receptor alpha (RARa) A B S T R A C TRetinoids are an important component of neuroblastoma therapy at the stage of minimal residual disease, yet 40e50% of patients treated with 13-cis-retinoic acid (13-cis-RA) still relapse, indicating the need for more effective retinoid therapy. Vorinostat, or Suberoylanilide hydroxamic acid (SAHA), is a potent inhibitor of histone deacetylase (HDAC) classes I & II and has antitumor activity in vitro and in vivo. Fenretinide (4-HPR) is a synthetic retinoid which acts on cancer cells through both nuclear retinoid receptor and non-receptor mechanisms. In this study, we found that the combination of 4-HPR þ SAHA exhibited potent cytotoxic effects on neuroblastoma cells, much more effective than 13-cis-RA þ SAHA. The 4-HPR þ SAHA combination induced caspase-dependent apoptosis through activation of caspase 3, reduced colony formation and cell migration in vitro, and tumorigenicity in vivo. The 4-HPR and SAHA combination significantly increased mRNA expression of thymosin-beta-4 (Tb4) and decreased mRNA expression of retinoic acid receptor a (RARa). Importantly, the up-regulation of Tb4 and down-regulation of RARa were both necessary for the 4-HPR þ SAHA cytotoxic effect on neuroblastoma cells. Moreover, Tb4 knockdown in neuroblastoma cells increased cell migration and blocked the effect of 4-HPR þ SAHA on cell migration and focal adhesion formation. In primary human neuroblastoma tumor tissues, low expression of Tb4 was associated with metastatic disease and predicted poor patient prognosis. Our findings demonstrate that Tb4 is a novel therapeutic target in neuroblastoma, and that 4-HPR þ SAHA is a potential therapy for the disease.

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Thymosin 4 has tumor suppressive effects and its decreased expression results in poor prognosis and decreased survival in multiple myeloma

Cited by 21 publications

References 26 publications

Shear force-based genetic screen reveals negative regulators of cell adhesion and protrusive activity

Shear force-based genetic screen reveals negative regulators of cell adhesion and protrusive activity

Preventive and therapeutic effects of thymosin β4 N-terminal fragment Ac-SDKP in the bleomycin model of pulmonary fibrosis

Thymosin‐β4 is a determinant of drug sensitivity for Fenretinide and Vorinostat combination therapy in neuroblastoma

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