Bone morphogenetic protein signalling is required for the anti‐mitogenic effect of the proteasome inhibitor MG‐132 on colon cancer cells

Wu, William; Sung, Joseph J.Y.; Wu, Yuzhong; Li, Z J; Yu, Li; Cho, C H

doi:10.1038/bjp.2008.115

Cited by 31 publications

(16 citation statements)

References 34 publications

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“…For example, MG132 affected the proliferation of lens epithelial cells (LECs) during the development of posterior capsular opacification (Awasthi and Wagner, 2006). In ovarian cancer cells, MG132 suppressed cell division in part by increasing the levels of p21 and p27 proteins (Bazzaro et al, 2006), while in gastric and colon cancer cells this inhibitor suppressed cell division via activation of BMP signaling (Wu et al, 2008). …”

Section: Discussionmentioning

confidence: 99%

Characterization of proteolytic activities during intestinal regeneration of the sea cucumber, Holothuria glaberrima

Pastén¹,

Rosa²,

Ortiz³

et al. 2012

Int. J. Dev. Biol.

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Proteolysis carried out by different proteases control cellular processes during development and regeneration. Here we investigated the function of the proteasome and other proteases in the process of intestinal regeneration using as a model the sea cucumber Holothuria glaberrima. This echinoderm possesses the ability to regenerate its viscera after a process of evisceration. Enzymatic activity assays showed that intestinal extracts at different stages of regeneration possessed chymotrypsin-like activity. This activity was inhibited by i) MG132, a reversible inhibitor of chymotrypsin and peptidylglutamyl peptidase hydrolase (PGPH) activities of the proteasome, ii) E64d, a permeable inhibitor of cysteine proteases and iii) TPCK, a serine chymotrypsin inhibitor, but not by epoxomicin, an irreversible and potent inhibitor of all enzymatic activities of the proteasome. To elucidate the role which these proteases might play during intestinal regeneration, we carried out in vivo experiments injecting MG132, E64d and TPCK into regenerating animals. The results showed effects on the size of the regenerating intestine, cell proliferation and collagen degradation. These findings suggest that proteolysis by several proteases is important in the regulation of intestinal regeneration in H. glaberrima.

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Section: Discussionmentioning

confidence: 99%

Characterization of proteolytic activities during intestinal regeneration of the sea cucumber, Holothuria glaberrima

Pastén¹,

Rosa²,

Ortiz³

et al. 2012

Int. J. Dev. Biol.

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“…Firstly, MG132 could inhibit the proteasome pathway mediated degradation of Smad proteins, and so contribute to the elevated Smad protein levels and enhance the activation of Smad proteins. Secondly, it has been shown that the expression of BMP-2 could be up-regulated by MG132 [49,50]. Thus, MG132, together with mechanical strain, might up-regulate BMP-2 expression, and this can lead to the increase in Smad activation and ALP expression.…”

Section: Discussionmentioning

confidence: 99%

Involvement of BMPs/Smad Signaling Pathway in Mechanical Response in Osteoblasts

Wang¹,

Zhang²,

Guo³

et al. 2010

Cell Physiol Biochem

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Background/Aims: Mechanical strain plays an important role in osteoblasts differentiation and bone formation but the underlying mechanism remains unclear. The aim of this study was to determine whether Bone Morphogenetic Proteins (BMPs)/Smad signaling pathway is involved in mechanical response in osteoblasts. Methods: MC3T3-E1 cells were exposed to mechanical strain via a four-point bending system. mRNA levels and protein levels of BMP-2, BMP-4, Smad1, Smad5, Smurf1, and Smurf2 were assessed using RT-PCR and immunoblotting. Protein levels of BMP-2 and BMP-4 in the culture medium were also determined using Enzyme-linked Immunosorbent Assay (ELISA). Pretreatment with Noggin and transfection with Smad4 siRNA were carried out to block the BMPs/Smad signaling pathway and MG132 was used to inhibit the proteasome pathway. Results: We found that mechanical strain enhanced alkaline phosphatase (ALP) expression and activated BMPs/Smad signaling pathway. Mechanical strain induced expression of ALP was attenuated by Noggin and by Smad4 siRNA. The protein levels of Smad1 and Smad5, but not their mRNA levels, were up-regulated by mechanical strain. This finding could be explained by the down-regulation of Smurf1. The protein degradation of Smad might be inhibited by mechanical strain through down-regulation of Smuf1 expression. The addition of MG132 further enhanced the mechanical strain induced activation of Smad proteins and the increased expression of ALP. Conclusions: Mechanical strain might promote osteoblasts differentiation through BMPs/Smad signaling pathway. The strain causes a drop in Smurf1 levels, leading to accumulation of Smad proteins and, subsequently, to enhanced BMPs/Smad signaling.

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“…Although BMPs are expressed in many tumors [25], no cases of malignancy have been reported as a direct result of BMP application. The effect of local application of BMPs in cases of existing malignancies remains controversial; a beneficial effect of BMP-7 or BMP signaling in inhibiting cancer cells has been reported [5,6,17,33], while other studies [18,19] have reported a negative effect. Several authors have indicated that OP-1 does not seem to have a carcinogenic effect [25,28,30].…”

Section: Discussionmentioning

confidence: 99%

Enhancement of Difficult Nonunion in Children with Osteogenic Protein-1 (OP-1): Early Experience

Dohin

Dahan‐Oliel

Fassier

et al. 2009

Clin Orthop Relat Res

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Numerous studies have described the use of osteogenic protein-1 (OP-1) in adults, but there are few reports in children. The objectives of this short-term followup cohort study were (1) to examine clinical and radiographic healing of persistent nonunions after OP-1 application in children; and (2) to determine the safety of OP-1 use in this sample. Clinical healing was defined by absence of pain and tenderness at the nonunion site and the ability to fully weight bear on the affected limb. Radiographic healing was determined by bony bridging of the nonunion site in at least one view. Safety was defined as the absence of major adverse events, including allergic reactions, infections, local inflammatory reactions, and heterotopic ossification. OP-1 was used in 19 patients who had an operative procedure for the bridging of persistent nonunions between 1999 and 2007. The mean age was 11.6 years (range, 4.8-20.3 years). Thirteen patients had persistent nonunion after one or more previous surgeries, prior to the initial OP-1 application. A single dose of 3.5 mg of OP-1 mixed with 1 g of Type I bovine collagen was applied to 23 sites of 19 patients. Three patients received additional OP-1 applications. Healing occurred clinically and radiographically in 17 of the 23 sites. Complications included four superficial pin site infections, one deep infection, and two fractures. No major local adverse event related to OP-1 application was noted in our sample. Our findings suggest OP-1 stimulates healing of persistent nonunions without major adverse events in our patient population. Level of Evidence: Level IV, case series. See the guidelines online for a complete description of levels of evidence.

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Bone morphogenetic protein signalling is required for the anti‐mitogenic effect of the proteasome inhibitor MG‐132 on colon cancer cells

Cited by 31 publications

References 34 publications

Characterization of proteolytic activities during intestinal regeneration of the sea cucumber, Holothuria glaberrima

Characterization of proteolytic activities during intestinal regeneration of the sea cucumber, Holothuria glaberrima

Involvement of BMPs/Smad Signaling Pathway in Mechanical Response in Osteoblasts

Enhancement of Difficult Nonunion in Children with Osteogenic Protein-1 (OP-1): Early Experience

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