Clusterin, a novel modulator of TGF-β signaling, is involved in Smad2/3 stability

Lee, Kwan-Bok; Jeon, Jun-Ho; Choi, Inpyo; Kwon, O‐Yu; Yu, Kweon; You, Kwan‐Hee

doi:10.1016/j.bbrc.2007.12.033

Cited by 51 publications

(30 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Akt inhibitors have been shown to induce cell apoptosis. (35) Here, we further confirmed that TCN highly significantly reduced the level of pAkt (Fig. 6A,B), and increased the apoptosis rates of both parental Bel7404 and Bel7404-sCLU high cells (Fig.…”

Section: Resultssupporting

confidence: 80%

Secretory clusterin contributes to oxaliplatin resistance by activating Akt pathway in hepatocellular carcinoma

Xiu

Dong

et al. 2013

Cancer Science

View full text Add to dashboard Cite

Secretory clusterin (sCLU) is expressed in numerous cancers and is associated with the resistance to chemotherapy. However, the role of sCLU in the resistance of hepatocellular carcinoma (HCC) to oxaliplatin (OXA), a recently used third-generation platinum agent, remains unclear. The stable transfectants that are depleted of or overexpress sCLU and OXA-resistant cells were generated using human HCC cells. Overexpression of sCLU abrogated OXAinduced inhibition of cell growth and cell apoptosis, but depletion of sCLU synergized with OXA to inhibit cell growth and enhance cell apoptosis, by regulating proteins involved in mitochondrial apoptosis pathways, such as Bcl-2, Bax, Bcl-xL and caspase-9, and affecting phosphorylation of Akt and GSK-3b. Overexpression of sCLU in either OXA-resistant cells or stable transfectants that overexpress sCLU significantly increased phosphorylated Akt. However, specific inhibition of Akt enhanced sensitivity of sCLU-overexpressing cells to OXA, but had no effect on sCLU expression, suggesting that the regulatory effects between sCLU and pAkt may be in a one-way manner in HCC cells. The expression levels of sCLU affected the therapeutic efficacy of OXA to treat HCC tumors established in immunodeficiency mice. The results have demonstrated that sCLU contributes to OXA resistance by activating Akt pathway, indicating that sCLU may be a novel molecular target for overcoming OXA resistance in HCC. (Cancer Sci 2013; 104: 375-382) L iver cancer is the second most frequent cause of cancer death in men worldwide, and hepatocellular carcinoma (HCC) accounts for 70-85% of all liver cancers.(1) However, HCC is extremely resistant to current chemotherapeutic drugs. Sorafenib is currently the most effective drug for HCC,but it prolongs survival for only 2-3 months, and has not been widely adopted because it is cost-prohibitive in Asia and subSaharan Africa, which have the highest incidence of HCC.(1) Therefore, novel drugs and therapeutic strategies for HCC continue to be sought.Oxaliplatin (OXA) is a third-generation platinum-derived chemotherapeutic agent that triggers cell death by inducing platinum-DNA adducts, and appears to block DNA replication more effectively than other platinum compounds.(3) OXA has been used to treat colorectal (4,5) and gastric (6) cancers, and has also displayed anti-tumor activity against HCC.(7) The combination of OXA and gemcitabine or bevacizumab has been investigated to treat advanced HCC in clinical trials, (8,9) but the results achieved were not comparable with the success obtained with colorectal cancer.(5) Furthermore, little data is available regarding the signaling pathways activated by OXA in HCC. Therefore, it remains a priority to find effective methods to enhance the sensitivity of HCC to OXA. Clusterin (CLU) was initially discovered as a secretory glycoprotein with cell-aggregating activity in vitro, (10) and is overexpressed in numerous advanced-stage and metastatic human cancers.(11) Overexpression of CLU has been observed in a majority of HCC ca...

show abstract

Section: Resultssupporting

confidence: 80%

Secretory clusterin contributes to oxaliplatin resistance by activating Akt pathway in hepatocellular carcinoma

Xiu

Dong

et al. 2013

Cancer Science

View full text Add to dashboard Cite

show abstract

“…47,48 In our encouraging WB results, the protein levels of the active forms phospho-Smad2 and phospho-Smad3 significantly increased in the PVA/COSAgNPs nanofiber group during the early stage of the healing progress. The protein expression levels of TGFβ1, collagen I, and collagen III exhibited trends that were consistent with their mRNA expression levels in the PVA/COS-AgNPs nanofiber group.…”

mentioning

confidence: 70%

Silver nanoparticles/chitosan oligosaccharide/poly(vinyl alcohol) nanofiber promotes wound healing by activating TGFβ1/Smad signaling pathway

Li¹,

Wang²,

Li³

et al. 2016

IJN

View full text Add to dashboard Cite

Wound healing occupies a remarkable place in everyday pathology and remains a challenging clinical problem. In our previous study, we prepared a silver nanoparticle/chitosan oligosaccharide/poly(vinyl alcohol) (PVA/COS-AgNPs) nanofiber via electrospinning and revealed that it could promote wound healing; however, the healing mechanism remained unknown. Therefore, we aimed to clarify the mechanism underlying the accelerated healing effect of the PVA/COS-AgNPs nanofiber. The TGFβ1/Smad signaling pathway is actively involved in wound healing. Considering the key role of this signaling pathway in wound healing, our preliminary study showed that the TGFβ1 level was significantly increased during the early stage of wound healing. Thus, in this study, hematoxylin–eosin, Masson’s trichrome, immunofluorescent staining, hydroxyproline content, quantitative real-time polymerase chain reaction, and Western blot analyses were used to analyze the wound healing in a rat model treated with gauze, the PVA/COS-AgNPs nanofiber, and the nanofiber plus SB431542 (an inhibitor of TGFβ1 receptor kinase). The results showed that the PVA/COS-AgNPs nanofiber promoted wound healing and upregulated the expression levels of cytokines associated with the TGFβ1/Smad signaling pathway such as TGFβ1, TGFβRI, TGFβRII, collagen I, collagen III, pSmad2, and pSmad3. Inhibiting this pathway with SB431542 resulted in prevention of the PVA/COS-AgNPs nanofiber-associated salutary effects on the early stage of wound healing and relative cytokines expression. In conclusion, the wound healing effect of the PVA/COS-AgNPs nanofiber involves activation of the TGFβ1/Smad signaling pathway.

show abstract

“…Howe, 1997Howe, , 1999 and as a marker for TGF-b1-mediated thyrocyte dedifferentiation (Wegrowski et al, 1999). In addition, intracellular clusterin has also been shown to interact with the C-terminus of the TGF-b receptors (Reddy et al, 1996) and to regulate Smad2/3 stability (Lee et al, 2008). Since our neutralizing antibodies can only target sCLU, it is unlikely that these other interactions are responsible for clusterin's EMT-promoting effects.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome profiling of a TGF-β-induced epithelial-to-mesenchymal transition reveals extracellular clusterin as a target for therapeutic antibodies

et al. 2009

View full text Add to dashboard Cite

Transforming growth factor (TGF)-b plays a dual role in tumorigenesis, switching from acting as a growth inhibitory tumor suppressor early in the process, to a tumor promoter in late-stage disease. Since TGF-b's prometastatic role may be linked to its ability to induce tumor cell epithelial-to-mesenchymal transition (EMT), we explored TGF-b's EMT-promoting pathways by analysing the transcriptome changes occurring in BRI-JM01 mammary tumor epithelial cells undergoing a TGF-b-induced EMT. We found the clusterin gene to be the most highly upregulated throughout most of the TGF-b time course, and showed that this results in an increase of the secreted form of clusterin. By monitoring several hallmark features of EMT, we demonstrated that antibodies targeting secreted clusterin inhibit the TGF-b-induced EMT of BRI-JM01 cells, as well as the invasive phenotype of several other breast and prostate tumor cell lines (4T1, NMuMG, MDA-MB231LM2 and PC3), without affecting the proliferation of these cells. These results indicate that secreted clusterin is a functionally important EMT mediator that lies downstream within TGF-b's EMTpromoting transcriptional cascade, but not within its growth-inhibitory pathways. To further investigate the role played by secreted clusterin in tumor metastasis, we assessed the effect of several anti-clusterin monoclonal antibodies in vivo using a 4T1 syngeneic mouse breast cancer model and found that these antibodies significantly reduce lung metastasis. Taken together, our results reveal a role for secreted clusterin as an important extracellular promoter of EMT, and suggest that antibodies targeting clusterin may inhibit tumor metastasis without reducing the beneficial growth inhibitory effects of TGF-b.

show abstract

Clusterin, a novel modulator of TGF-β signaling, is involved in Smad2/3 stability

Cited by 51 publications

References 27 publications

Secretory clusterin contributes to oxaliplatin resistance by activating Akt pathway in hepatocellular carcinoma

Secretory clusterin contributes to oxaliplatin resistance by activating Akt pathway in hepatocellular carcinoma

Silver nanoparticles/chitosan oligosaccharide/poly(vinyl alcohol) nanofiber promotes wound healing by activating TGFβ1/Smad signaling pathway

Transcriptome profiling of a TGF-β-induced epithelial-to-mesenchymal transition reveals extracellular clusterin as a target for therapeutic antibodies

Contact Info

Product

Resources

About

Clusterin, a novel modulator of TGF-β signaling, is involved in Smad2/3 stability

Cited by 51 publications

References 27 publications

Secretory clusterin contributes to oxaliplatin resistance by activating Akt pathway in hepatocellular carcinoma

Secretory clusterin contributes to oxaliplatin resistance by activating Akt pathway in hepatocellular carcinoma

Silver nanoparticles/chitosan oligosaccharide/poly(vinyl alcohol) nanofiber promotes wound healing by activating TGF&beta;1/Smad signaling pathway

Transcriptome profiling of a TGF-β-induced epithelial-to-mesenchymal transition reveals extracellular clusterin as a target for therapeutic antibodies

Contact Info

Product

Resources

About

Silver nanoparticles/chitosan oligosaccharide/poly(vinyl alcohol) nanofiber promotes wound healing by activating TGFβ1/Smad signaling pathway