| 1. |
- Ahlqvist, Kristofer, et al.
(författare)
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Expression of Id proteins is regulated by the Bcl-3 proto-oncogene in prostate cancer.
- 2013
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 1476-5594 .- 0950-9232. ; 32:12, s. 1601-1608
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Tidskriftsartikel (refereegranskat)abstract
- B-cell leukemia 3 (Bcl-3) is a member of the inhibitor of κB family, which regulates a wide range of biological processes by functioning as a transcriptional activator or as a repressor of target genes. As high levels of Bcl-3 expression and activation have been detected in different types of human cancer, Bcl-3 has been labeled a proto-oncogene. Our study uncovered a markedly upregulated Bcl-3 expression in human prostate cancer (PCa), where inflammatory cell infiltration was observed. Elevated Bcl-3 expression in PCa was dependent on the proinflammatory cytokine interleukin-6-mediated STAT3 activation. Microarray analyses, using Bcl-3 knockdown in PCa cells, identified the inhibitor of DNA-binding (Id) family of helix-loop-helix proteins as potential Bcl-3-regulated genes. Bcl-3 knockdown reduced the abundance of Id-1 and Id-2 proteins and boosted PCa cells to be more receptive to undergoing apoptosis following treatment with anticancer drug. Our data imply that inactivation of Bcl-3 may lead to sensitization of cancer cells to chemotherapeutic drug-induced apoptosis, thus suggesting a potential therapeutic strategy in PCa treatment.Oncogene advance online publication, 14 May 2012; doi:10.1038/onc.2012.175.
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| 2. |
- Saamarthy, Karunakar, et al.
(författare)
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Discovery of a small molecule that inhibits Bcl-3-mediated cyclin D1 expression in melanoma cells
- 2024
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Ingår i: BMC Cancer. - 1471-2407. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- Molecular targeted therapy using a drug that suppresses the growth and spread of cancer cells via inhibition of a specific protein is a foundation of precision medicine and treatment. High expression of the proto-oncogene Bcl-3 promotes the proliferation and metastasis of cancer cells originating from tissues such as the colon, prostate, breast, and skin. The development of novel drugs targeting Bcl-3 alone or in combination with other therapies can cure these patients or prolong their survival. As a proof of concept, in the present study, we focused on metastatic melanoma as a model system. High-throughput screening and in vitro experiments identified BCL3ANT as a lead molecule that could interfere with Bcl-3-mediated cyclin D1 expression and cell proliferation and migration in melanoma. In experimental animal models of melanoma, it was demonstrated that the use of a Bcl-3 inhibitor can influence the survival of melanoma cells. Since there are no other inhibitors against Bcl-3 in the clinical pipeline for cancer treatment, this presents a unique opportunity to develop a highly specific drug against malignant melanoma to meet an urgent clinical need.
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| 3. |
- Saamarthy, Karunakar, et al.
(författare)
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Early diagnostic value of Bcl-3 localization in colorectal cancer
- 2015
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Ingår i: Bmc Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 15:341
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Tidskriftsartikel (refereegranskat)abstract
- Background: B-cell leukemia 3 (Bcl-3) is a member of the inhibitor of kappa B family, which regulates a wide range of biological processes by functioning as a transcriptional activator or as a repressor of target genes. Elevated expression, sustained nuclear accumulation, and uncontrolled activation of Bcl-3 causes increased cellular proliferation or survival, dependent on the tissue and type of stimuli. Methods: We retrospectively reviewed patients who were diagnosed with colorectal cancer at Skane University Hospital in Malmo between 1st of January 1990 and 31st of December 1991. Bcl-3 localization in colorectal cancer was assessed by immunohistochemistry on tissue microarray and freshly isolated colon from patients. Correlation between Bcl-3 localization and clinicopathological parameters of the cohort were evaluated using the Spearman rank-order correlation coefficient. In addition, Bcl-3 expression and localization in colon adenocarcinoma cells were analysed by western blot, immunohistochemistry and subcellular fractionation separately. Results: We found that Bcl-3 was mainly localized in the cytoplasm in the tumour tissue isolated from colon cancer patients. Normal colon samples from the same patients showed Bcl-3 localization in the nucleus. In three out of six colon cancer cell lines, we detected elevated levels of Bcl-3. In these cell lines Bcl-3 was accumulated in the cytosol. We confirmed these findings by analysing Bcl-3 localization in a colon tissue micro array consisting of 270 cases. In these samples Bcl-3 localization correlated with the proliferation marker Ki-67, but not with the apoptotic marker Caspase 3. Conclusion: These findings indicate that analysis of the subcellular localization of Bcl-3 could be a potential-early diagnostic marker in colon cancer.
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| 4. |
- Saamarthy, Karunakar
(författare)
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The impact of Bcl-3 expression and signaling in cancer
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Bcl-3 is a proto-oncogene and belongs to the inhibitor of κB (IκB) family and is known to be upregulated in numerous cancers. Bcl-3 can initiate transcription of different genes involved in cell survival and cell growth. Cell proliferation is achieved through binding of Bcl-3 to cyclin D1 promoter and facilitates the rapid transition from G1 to S phase. The aim of this thesis was to investigate the role of Bcl-3 in different types of cancers including prostate, colon, and melanoma as well as to identify a selective inhibitor against Bcl-3 protein. In prostate cancer (PC) we observed the upregulation of Bcl-3 in cancer cells adjacent to infiltration of inflammatory cells. More precisely in PC cell lines we found out that Bcl-3 was upregulated with the stimulation of IL-6 through STAT3 signaling pathway. Silencing of Bcl-3 in PC cell lines sensitize these cells against anticancer drugs treatment and formed small tumors in vivo compared to control treated cells. In colon cancer we found that Bcl-3 localization differed comparing non-cancerous with cancer cells. Bcl-3 was mainly localized in cytoplasm of cancer tissue compared to nucleus in normal colon tissue. Out of six colon cancer lines three of them showed highest expression of Bcl-3. Cell fractionation analysis of these cell lines reiterated that majority of Bcl-3 protein was localized in the cytoplasm. Furthermore, the cytoplasmic localization of Bcl-3 in cancer cells correlated positively with proliferation marker Ki67 but not with the apoptotic marker cleaved caspase 3. Results obtained from this study suggest that cytoplasmic presence of Bcl-3 could be used as a diagnostic marker in certain stages of colon cancer. Since so far no inhibitors against Bcl-3 exist, we decided to identify a specific inhibitor against Bcl-3 protein. For this purpose we screened among 1368 synthetic compounds and could identify a specific Bcl-3 inhibitor. Treatment of melanoma cells with Bcl-3 inhibitor or its related derivate reduced the proliferation and arrested cells at G1/S phase of the cell cycle. Results from this study suggest that our newly identified Bcl-3 inhibitor can be used as anticancer drug to reduce the proliferation in melanoma.
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| 5. |
- Stenvall, Jörgen, et al.
(författare)
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Selenoprotein TRXR-1 and GSR-1 are essential for removal of old cuticle during molting in Caenorhabditis elegans
- 2011
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 108:3, s. 1064-1069
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Tidskriftsartikel (refereegranskat)abstract
- Selenoproteins, in particular thioredoxin reductase, have been implicated in countering oxidative damage occurring during aging but the molecular functions of these proteins have not been extensively investigated in different animal models. Here we demonstrate that TRXR-1 thioredoxin reductase, the sole selenoprotein in Caenorhabditis elegans, does not protect against acute oxidative stress but functions instead together with GSR-1 glutathione reductase to promote the removal of old cuticle during molting. We show that the oxidation state of disulfide groups in the cuticle is tightly regulated during the molting cycle, and that when trxr-1 and gsr-1 function is reduced, disulfide groups in the cuticle remain oxidized. A selenocysteine-to-cysteine TRXR-1 mutant fails to rescue molting defects. Furthermore, worms lacking SELB-1, the C. elegans homolog of Escherichia coli SelB or mammalian EFsec, a translation elongation factor known to be specific for selenocysteine in E. coli, fail to incorporate selenocysteine, and display the same phenotype as those lacking trxr-1. Thus, TRXR-1 function in the reduction of old cuticle is strictly selenocysteine dependent in the nematode. Exogenously supplied reduced glutathione reduces disulfide groups in the cuticle and induces apolysis, the separation of old and new cuticle, strongly suggesting that molting involves the regulated reduction of cuticle components driven by TRXR-1 and GSR-1. Using dauer larvae, we demonstrate that aged worms have a decreased capacity to molt, and decreased expression of GSR-1. Together, our results establish a function for the selenoprotein TRXR-1 and GSR-1 in the removal of old cuticle from the surface of epidermal cells.
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