AIM： To evaluate the expression of C-X-C motif chemokine receptor 4 （CXCR4） and its signaling cascades, which were previously identified as a key factor for cancer cell progression and metastasis, in cholangiocarci...AIM： To evaluate the expression of C-X-C motif chemokine receptor 4 （CXCR4） and its signaling cascades, which were previously identified as a key factor for cancer cell progression and metastasis, in cholangiocarcinoma cell lines. METHODS： The expression of CXCR4 and its signaling cascades were determined in the cholangiocarcinoma cell lines （RMCCA1 and KKU100） by Western blotting. The invasion assays and the detection of actin polymerization were tested in these cholangiocarcinoma cells treated with CXC chemokine ligand -12 （CXCL12）. RESULTS： Expression of CXCR4 was detected in both cholangiocarcinoma cell lines and activation of CXCR4 with CXCL12 triggered the signaling via the extracellular signal-regulated kinase-1/2 （ERK1/2） and phosphoinositide 3-kinase （PI3K） and induction of cholangiocarcinoma cell invasion, and displayed high levels of actin polymerization. Addition of CXCR4 inhibitor （AMD3100） abrogated CXCL12-induced phosphorylation of MEKI/2 and Akt in these cells. Moreover, treatment with MEK1/2 inhibitor （U0126） or PI3K inhibitor （LY294002） also attenuated the effect of CXCL12- induced cholangiocarcinoma cell invasion. CONCLUSION： These results indicated that the activation of CXCR4 and its signaling pathways （MEK1/2 and Akt） are essential for CXCL12-induced cholangiocarcinoma cell invasion. This rises Implications on a potential role for the inhibition of CXCR4 or its signal cascades in the treatment of cholangiocarcinoma.展开更多
Adiponectin(APN), an adipokine produced by adipocytes, has been shown to have a critical role in the pathogenesis of obesityassociated malignancies. Through its receptor interactions, APN may exert its anti-carcinogen...Adiponectin(APN), an adipokine produced by adipocytes, has been shown to have a critical role in the pathogenesis of obesityassociated malignancies. Through its receptor interactions, APN may exert its anti-carcinogenic effects including regulating cell survival, apoptosis and metastasis via a plethora of signalling pathways. Despite the strong evidence supporting this notion, some work may indicate otherwise. Our review addresses all controversies critically. On the whole, hypoadiponectinaemia is associated with increased risk of several malignancies and poor prognosis. In addition, various genetic polymorphisms may predispose individuals to increased risk of obesity-associated malignancies. We also provide an updated summary on therapeutic interventions to increase APN levels that are of key interest in this field. To date efforts to manipulate APN levels have been promising, but much work remains to be done.展开更多
Objective： Chronic lymphocytic leukemia （CLL） and mantle cell lymphoma （MCL） cells over-express a guanine exchange factor （GEF）, Rasgrf-1. This GEF increases active Ras as it catalyzes the removal of GDP from R...Objective： Chronic lymphocytic leukemia （CLL） and mantle cell lymphoma （MCL） cells over-express a guanine exchange factor （GEF）, Rasgrf-1. This GEF increases active Ras as it catalyzes the removal of GDP from Ras so that GTP can bind and activate Ras. This study aims to study the mechanism of action of Rasgrf-1 in B-cell malignancies. Methods： N-terminus truncated Rasgrf-1 variants have a higher GEF activity as compared to the full-length transcript therefore a MCL cell line with stable over-expression of truncated Rasgrf-1 was established. The B-cell receptor （BCR） and chemokine signaling pathways were compared in the Rasgrf-I over-expressing and a control transfected cell line. Results： Cells over-expressing truncated form of Rasgrf-1 have a higher proliferative rate as compared to control transfected cells. BCR was activated by lower concentrations of anti-IgM antibody in Rasgrf-1 over-expressing cells as compared to control cells indicating that these cells are more sensitive to BCR signaling. BCR signaling also phosphorylates Rasgrf-1 that further increases its GEF function and amplifies BCR signaling. This activation of Rasgrf-1 in over-expressing cells resulted in a higher expression of phospho-ERK, AKT, BTK and PKC-alpha as compared to control cells. Besides BCR, Rasgrf-1 over-expressing cells were also more sensitive to microenvironment stimuli as determined by resistance to apoptosis, chemotaxis and ERK pathway activation. Conclusions： This GEF protein sensitizes B-cells to BCR and chemokine mediated signaling and also upregulates a number of other signaling pathways which promotes growth and survival of these cells.展开更多
In this study,three kinds of phenothiazine drugs were analyzed to explore their potential antitumor mechanisms.First,target proteins that could interact with chlorpromazine,fluphenazine and trifluoperazine were predic...In this study,three kinds of phenothiazine drugs were analyzed to explore their potential antitumor mechanisms.First,target proteins that could interact with chlorpromazine,fluphenazine and trifluoperazine were predicted.Then,the target proteins of the three drugs were intersected.Cell signaling pathway enrichment and related disease enrichment were conducted for the intersected proteins to extract the enrichment categories associated with tumors.By regulation network analysis of the protein interactions,the mechanisms of action of these target proteins in tumor tissue were clarified,thus confirming the potential antitumor mechanisms of the phenothiazine drugs.The final results of cell signaling pathway enrichment and related disease enrichment showed that the categories with the highest score were all found in tumors.Target proteins belonging to the tumor category included signaling pathway members such as Wnt,MAPK and retinoic acid receptor.Moreover,another target protein,MAPK8,could indirectly act on target proteins CDK2,IGF1R,GSK3B,RARA,FGFR2 and MAPK10,thereby affecting tumor cell division and proliferation.Therefore,phenothiazine drugs may have potential antitumor effects,and tumorassociated target proteins play important roles in the process of cell signaling transduction cascades.展开更多
基金Supported by the Grant from National Center for Genetic Engineering and Biotechnology,Thailand and Rajavithi HospitalFund
文摘AIM： To evaluate the expression of C-X-C motif chemokine receptor 4 （CXCR4） and its signaling cascades, which were previously identified as a key factor for cancer cell progression and metastasis, in cholangiocarcinoma cell lines. METHODS： The expression of CXCR4 and its signaling cascades were determined in the cholangiocarcinoma cell lines （RMCCA1 and KKU100） by Western blotting. The invasion assays and the detection of actin polymerization were tested in these cholangiocarcinoma cells treated with CXC chemokine ligand -12 （CXCL12）. RESULTS： Expression of CXCR4 was detected in both cholangiocarcinoma cell lines and activation of CXCR4 with CXCL12 triggered the signaling via the extracellular signal-regulated kinase-1/2 （ERK1/2） and phosphoinositide 3-kinase （PI3K） and induction of cholangiocarcinoma cell invasion, and displayed high levels of actin polymerization. Addition of CXCR4 inhibitor （AMD3100） abrogated CXCL12-induced phosphorylation of MEKI/2 and Akt in these cells. Moreover, treatment with MEK1/2 inhibitor （U0126） or PI3K inhibitor （LY294002） also attenuated the effect of CXCL12- induced cholangiocarcinoma cell invasion. CONCLUSION： These results indicated that the activation of CXCR4 and its signaling pathways （MEK1/2 and Akt） are essential for CXCL12-induced cholangiocarcinoma cell invasion. This rises Implications on a potential role for the inhibition of CXCR4 or its signal cascades in the treatment of cholangiocarcinoma.
文摘Adiponectin(APN), an adipokine produced by adipocytes, has been shown to have a critical role in the pathogenesis of obesityassociated malignancies. Through its receptor interactions, APN may exert its anti-carcinogenic effects including regulating cell survival, apoptosis and metastasis via a plethora of signalling pathways. Despite the strong evidence supporting this notion, some work may indicate otherwise. Our review addresses all controversies critically. On the whole, hypoadiponectinaemia is associated with increased risk of several malignancies and poor prognosis. In addition, various genetic polymorphisms may predispose individuals to increased risk of obesity-associated malignancies. We also provide an updated summary on therapeutic interventions to increase APN levels that are of key interest in this field. To date efforts to manipulate APN levels have been promising, but much work remains to be done.
文摘Objective： Chronic lymphocytic leukemia （CLL） and mantle cell lymphoma （MCL） cells over-express a guanine exchange factor （GEF）, Rasgrf-1. This GEF increases active Ras as it catalyzes the removal of GDP from Ras so that GTP can bind and activate Ras. This study aims to study the mechanism of action of Rasgrf-1 in B-cell malignancies. Methods： N-terminus truncated Rasgrf-1 variants have a higher GEF activity as compared to the full-length transcript therefore a MCL cell line with stable over-expression of truncated Rasgrf-1 was established. The B-cell receptor （BCR） and chemokine signaling pathways were compared in the Rasgrf-I over-expressing and a control transfected cell line. Results： Cells over-expressing truncated form of Rasgrf-1 have a higher proliferative rate as compared to control transfected cells. BCR was activated by lower concentrations of anti-IgM antibody in Rasgrf-1 over-expressing cells as compared to control cells indicating that these cells are more sensitive to BCR signaling. BCR signaling also phosphorylates Rasgrf-1 that further increases its GEF function and amplifies BCR signaling. This activation of Rasgrf-1 in over-expressing cells resulted in a higher expression of phospho-ERK, AKT, BTK and PKC-alpha as compared to control cells. Besides BCR, Rasgrf-1 over-expressing cells were also more sensitive to microenvironment stimuli as determined by resistance to apoptosis, chemotaxis and ERK pathway activation. Conclusions： This GEF protein sensitizes B-cells to BCR and chemokine mediated signaling and also upregulates a number of other signaling pathways which promotes growth and survival of these cells.
文摘In this study,three kinds of phenothiazine drugs were analyzed to explore their potential antitumor mechanisms.First,target proteins that could interact with chlorpromazine,fluphenazine and trifluoperazine were predicted.Then,the target proteins of the three drugs were intersected.Cell signaling pathway enrichment and related disease enrichment were conducted for the intersected proteins to extract the enrichment categories associated with tumors.By regulation network analysis of the protein interactions,the mechanisms of action of these target proteins in tumor tissue were clarified,thus confirming the potential antitumor mechanisms of the phenothiazine drugs.The final results of cell signaling pathway enrichment and related disease enrichment showed that the categories with the highest score were all found in tumors.Target proteins belonging to the tumor category included signaling pathway members such as Wnt,MAPK and retinoic acid receptor.Moreover,another target protein,MAPK8,could indirectly act on target proteins CDK2,IGF1R,GSK3B,RARA,FGFR2 and MAPK10,thereby affecting tumor cell division and proliferation.Therefore,phenothiazine drugs may have potential antitumor effects,and tumorassociated target proteins play important roles in the process of cell signaling transduction cascades.
