| 1. |
- Bellamkonda, Kishan, et al.
(författare)
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Montelukast, a CysLT1 receptor antagonist, reduces colon cancer stemness and tumor burden in a mouse xenograft model of human colon cancer
- 2018
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Ingår i: Cancer Letters. - : Elsevier BV. - 0304-3835. ; 437, s. 13-24
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Tidskriftsartikel (refereegranskat)abstract
- Inflammation is implicated in the etiology of sporadic colon cancer (CC), which is one of the leading causes of cancer-related deaths worldwide. Here, we report that inhibition of the inflammatory receptor CysLT1 through its antagonist, montelukast, is beneficial in minimizing stemness in CC and thereby minimizing tumor growth in a mouse xenograft model of human colon cancer. Upon treatment with montelukast, colonospheres derived from HT-29 and SW-480 human colon cancer cells exhibited a significant phenotypic change coupled with the downregulation of mRNA and protein expression of cancer stem cell (CSC) markers ALDH1 and DCLK1. Moreover, montelukast reduced the size of HT-29 cell-derived tumors in mice. The reduction in tumor size was associated with decreased levels of ALDH1A1, DCLK1, BCL2 mRNA and macrophage infiltration into the tumor tissue. Interestingly, this treatment elevated levels of the tumor suppressor 15-PGDH while reducing COX-2 expression. Our data highlight the association of CysLT1R with CSCs and demonstrate that inhibition of CysLT1R could prove beneficial in minimizing CSC-induced tumor growth. This work advances the notion that targeting CSCs is a promising approach to improve outcomes in those afflicted with colon cancer.
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| 2. |
- Bellamkonda, Kishan, et al.
(författare)
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The eicosanoids leukotriene D4 and prostaglandin E2 promote the tumorigenicity of colon cancer-initiating cells in a xenograft mouse model
- 2016
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Colorectal cancer is one of the most common types of cancers worldwide. Recent studies have identified cancer-initiating cells (CICs) as a subgroup of replication-competent cells in the development of colorectal cancer. Although it is understood that an inflammation-rich tumor microenvironment presumably supports CIC functions, the contributory factors are not very well defined. The present study advances our understanding of the role of the eicosanoids leukotriene D4 (LTD4) and prostaglandin E2 (PGE2) in the tumorigenic ability of CICs and investigates the consequential changes occurring in the tumor environment that might support tumor growth. Methods: In this study we used human HCT-116 colon cancer ALDH+ cells in a nude mouse xenograft model. Protein expression and immune cell was determined in tumor-dispersed cells by flow cytometry and in tumor sections by immunohistochemistry. mRNA expressions were quantified using RT-q-PCR and plasma cytokine levels by Multiplex ELISA. Results: We observed that LTD4 and PGE2 treatment augmented CIC-induced tumor growth. LTD4-and PGE2-treated xenograft tumors revealed a robust increase in ALDH and Dclk1 protein expression, coupled with activated β-catenin signaling and COX-2 up-regulation. Furthermore, LTD4 or PGE2 accentuated the accumulation of CD45 expressing cells within xenograft tumors. Further analysis revealed that these infiltrating immune cells consisted of neutrophils (LY6G) and M2 type macrophages (CD206+). In addition, LTD4 and PGE2 treatment significantly elevated the plasma levels of cysteinyl leukotrienes and PGE2, as well as levels of IL-1β, IL-2, IL-6, TNF-α and CXCL1/KC/GRO. In addition, increased mRNA expression of IL-1β, IL-6 and IL-10 were detected in tumors from mice that had been treated with LTD4 or PGE2. Conclusion: Our data suggest that both LTD4 and PGE2 promote CICs in initiating tumor growth by allowing modifications in the tumor environment. Our data indicate that new therapeutic strategies targeting eicosanoids, specifically LTD4 and PGE2, could be tested for better therapeutic management of colon cancer.
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| 3. |
- Bellamkonda, Kishan, et al.
(författare)
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The impact of inflammatory lipid mediators on colon cancer-initiating cells.
- 2015
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Ingår i: Molecular Carcinogenesis. - : Wiley. - 1098-2744 .- 0899-1987. ; 54:11, s. 1315-1327
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Tidskriftsartikel (refereegranskat)abstract
- The role of inflammatory lipid-mediators in tumor progression is well recognized in colorectal cancer; however, if this includes promotion of cancer-initiating cells remains unclear. We show that the inflammatory lipid-mediators leukotriene D4 and prostaglandin E2 increased the Aldehyde dehydrogenase (ALDH(+) ) population, the colony formation capacity, and tumor growth in a xenograft model of colon cancer. The ALDH(+) cells showed significant resistance to irradiation and 5-fluorouracil treatment that could be further augmented by these lipid-mediators, occurring in parallel with increased target gene expression. Our data emphasize a role for tumor microenvironment derived inflammatory lipid-mediators to favor cancer stem cells-like characteristics and thus promote tumor progression. © 2014 Wiley Periodicals, Inc.
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| 4. |
- Bengtsson, Astrid, et al.
(författare)
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Leukotriene D(4) induces AP-1 but not NFkappaB signaling in intestinal epithelial cells.
- 2008
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Ingår i: Prostaglandins & other Lipid Mediators. - : Elsevier BV. - 1098-8823. ; 85:3-4, s. 100-106
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Tidskriftsartikel (refereegranskat)abstract
- We have previously shown that leukotriene D(4) (LTD(4)), a known pro-inflammatory mediator, induces increased survival and proliferation of intestinal epithelial cells. In this study we examined whether LTD(4) functions via activation of the transcription factors NFkappaB and AP-1, which are potent inducers of mitogenesis. We found that the NFkappaB inhibitory protein IkappaBalpha was not degraded upon LTD(4) stimulation. Furthermore, nuclear translocation of the classical p65 or alternative p52 subunits of NFkappaB was not observed. Accordingly, LTD(4) stimulation failed to induce NFkappaB transcriptional activity. Instead we found that LTD(4) induced phosphorylation of c-Jun-N-terminal kinase (JNK) and transcriptional activity of AP-1, which could be reduced by a JNK inhibitor. Moreover, LTD(4) induced cell proliferation, and this effect was also blocked upon addition of a JNK inhibitor. Our findings show for the first time that JNK/AP-1 but not NFkappaB is a downstream target of LTD(4) in intestinal epithelial cells, suggesting that AP-1 is an important mediator of LTD(4)-induced mitogenic effects.
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| 5. |
- Bengtsson, Astrid, et al.
(författare)
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The cysteinyl leukotriene 2 receptor contributes to all-trans retinoic acid-induced differentiation of colon cancer cells
- 2013
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cysteinyl leukotrienes (CysLTs) are potent pro-inflammatory mediators that are increased in samples from patients with inflammatory bowel diseases (IBDs). Individuals with IBDs have enhanced susceptibility to colon carcinogenesis. In colorectal cancer, the balance between the pro-mitogenic cysteinyl leukotriene 1 receptor (CysLT(1)R) and the differentiation-promoting cysteinyl leukotriene 2 receptor (CysLT(2)R) is lost. Further, our previous data indicate that patients with high CysLT(1)R and low CysLT(2)R expression have a poor prognosis. In this study, we examined whether the balance between CysLT(1)R and CysLT(2)R could be restored by treatment with the cancer chemopreventive agent all-trans retinoic acid (ATRA). Methods: To determine the effect of ATRA on CysLT(2)R promoter activation, mRNA level, and protein level, we performed luciferase gene reporter assays, real-time polymerase chain reactions, and Western blots in colon cancer cell lines under various conditions. Results: ATRA treatment induces CysLT(2)R mRNA and protein expression without affecting CysLT(1)R levels. Experiments using siRNA and mutant cell lines indicate that the up-regulation is retinoic acid receptor (RAR) dependent. Interestingly, ATRA also up-regulates mRNA expression of leukotriene C-4 synthase, the enzyme responsible for the production of the ligand for CysLT(2)R. Importantly, ATRA-induced differentiation of colorectal cancer cells as shown by increased expression of MUC-2 and production of alkaline phosphatase, both of which could be reduced by a CysLT(2)R-specific inhibitor. Conclusions: This study identifies a novel mechanism of action for ATRA in colorectal cancer cell differentiation and demonstrates that retinoids can have anti-tumorigenic effects through their action on the cysteinyl leukotriene pathway.
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| 6. |
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| 7. |
- Björnström, Karin, 1971-, et al.
(författare)
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A tyrosine kinase regulates propofol-induced modulation of the beta-subunit of the GABA(A) receptor and release of intracellular calcium in cortical rat neurones
- 2002
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Ingår i: Acta Physiologica Scandinavica. - 0001-6772 .- 1365-201X. ; 175:3, s. 227-235
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Tidskriftsartikel (refereegranskat)abstract
- Propofol, an intravenous anaesthetic, has been shown to interact with the beta -subunit of the gamma -amino butyric acid(A) (GABA(A) ) receptor and also to cause changes in [Ca2+ ](i) . The GABA(A) receptor, a suggested target for anaesthetics, is known to be regulated by kinases. We have investigated if tyrosine kinase is involved in the intracellular signal system used by propofol to cause anaesthesia. We used primary cell cultured neurones from newborn rats, pre-incubated with or without a tyrosine kinase inhibitor before propofol stimulation. The effect of propofol on tyrosine phosphorylation and changes in [Ca2+ ](i) were investigated. Propofol (3 mu g mL(-1) , 16.8 mu M) increased intracellular calcium levels by 122 +/- 34% (mean +/- SEM) when applied to neurones in calcium free medium. This rise in [Ca2+ ](i) was lowered by 68% when the cells were pre-incubated with the tyrosine kinase inhibitor herbimycin A before exposure to propofol (P < 0.05). Propofol caused an increase (33 +/- 10%) in tyrosine phosphorylation, with maximum at 120 s, of the beta -subunit of the GABA(A) -receptor. This tyrosine phosphorylation was decreased after pre-treatment with herbimycin A (44 +/- 7%, P < 0.05), and was not affected by the absence of exogenous calcium in the medium. Tyrosine kinase participates in the propofol signalling system by inducing the release of calcium from intracellular stores and by modulating the beta -subunit of the GABA(A) -receptor.
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| 8. |
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| 9. |
- Broom, Oliver, et al.
(författare)
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CD47 regulates collagen I-induced cyclooxygenase-2 expression and intestinal epithelial cell migration.
- 2009
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 4:7, s. e6371-
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Tidskriftsartikel (refereegranskat)abstract
- Increased epithelial cell expression of the cyclooxygenase-2 (COX-2) enzyme is a characteristic event of both inflammatory bowel disease and colon cancer. We here report the novel findings that collagen I-induced de novo synthesis of COX-2 in intestinal epithelial cells is inhibited by pertussis toxin (PTX) and by an inhibitory peptide selective for the heterotrimeric G alpha(i3)-protein. These findings could be explained by a regulatory involvement of the G-protein-dependent integrin-associated protein CD47. In support of this notion, we observed a collagen I-induced association between CD47 and alpha2 integrins. This association was reduced by a blocking anti-CD47 antibody but not by PTX or a control anti-beta2 antibody. Furthermore, a blocking antibody against CD47, dominant negative CD47 or specific siRNA knock down of CD47, significantly reduced collagen I-induced COX-2 expression. COX-2 has previously been shown to regulate intestinal epithelial cell adhesion and migration. Morphological analysis of intestinal cells adhering to collagen I revealed a co-localisation of CD47 and alpha2 integrins to non-apoptotic membrane blebs enriched in Rho A and F-actin. The blocking CD47 antibody, PTX and a selective COX-2 inhibitor, dramatically inhibited the formation of these blebs. In accordance, migration of these cells on a collagen I-coated surface or through a collagen I gel were significantly reduced by the CD47 blocking antibody, siRNA knock down of CD47 and the COX-2 inhibitor NS-398. In conclusion, we present novel data that identifies the G-protein-dependent CD47 protein as a key regulator of collagen I-induced COX-2 expression and a promoter of intestinal epithelial cell migration.
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| 10. |
- Dash, Pujarini, et al.
(författare)
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High PGD2 receptor 2 levels are associated with poor prognosis in colorectal cancer patients and induce VEGF expression in colon cancer cells and migration in a zebrafish xenograft model
- 2022
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 126:4, s. 586-597
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Tidskriftsartikel (refereegranskat)abstract
- Background: Despite intense research, the prognosis for patients with advanced colorectal cancer (CRC) remains poor. The prostaglandin D2 receptors DP1 and DP2 are explored here as potential therapeutic targets for advanced CRC. Methods: A CRC cohort was analysed to determine whether DP1 and DP2 receptor expression correlates with patient survival. Four colon cancer cell lines and a zebrafish metastasis model were used to explore how DP1/DP2 receptor expression correlates with CRC progression. Results: Analysis of the clinical CRC cohort revealed high DP2 expression in tumour tissue, whereas DP1 expression was low. High DP2 expression negatively correlated with overall survival. Other pathological indicators, such as TNM stage and metastasis, positively correlated with DP2 but not DP1 expression. In accordance, the in vitro results showed high DP2 expression in four CC-cell lines, but only one expressed DP1. DP2 stimulation resulted in increased proliferation, p-ERK1/2 and VEGF expression/secretion. DP2-stimulated cells exhibited increased migration in the zebrafish metastasis model. Conclusion: Our results support DP2 receptor expression and signalling as a therapeutic target in CRC progression based on its expression in CRC tissue correlating with poor patient survival and that it triggers proliferation, p-ERK1/2 and VEGF expression and release and increased metastatic activity in CC-cells.
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