A potential anti-tumor effect of leukotriene C4 through the induction of 15-hydroxyprostaglandin dehydrogenase expression in colon cancer cells

Mehdawi, Lubna M.; Satapathy, Shakti Ranjan; Gustafsson, Annika; Lundholm, Kent; Alvarado-Kristensson, María; Sjölander, Anita

doi:10.18632/oncotarget.16591

Cited by 23 publications

(33 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Both receptors are not highly expressed in normal uveal tract [ 51 ], which suggests a role in early carcinogenesis. Of note, high CysLT 1 expression is associated with poor prognosis and reduced survival in both colorectal [ 28 ] and breast cancer [ 29 ], while CysLT 2 has been reported to have an anti-tumorigenic effect in colorectal cancer [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

High Cysteinyl Leukotriene Receptor 1 Expression Correlates with Poor Survival of Uveal Melanoma Patients and Cognate Antagonist Drugs Modulate the Growth, Cancer Secretome, and Metabolism of Uveal Melanoma Cells

Slater

Heeran

García-Mulero

et al. 2020

Cancers

View full text Add to dashboard Cite

Metastatic uveal melanoma (UM) is a rare, but often lethal, form of ocular cancer arising from melanocytes within the uveal tract. UM has a high propensity to spread hematogenously to the liver, with up to 50% of patients developing liver metastases. Unfortunately, once liver metastasis occurs, patient prognosis is extremely poor with as few as 8% of patients surviving beyond two years. There are no standard-of-care therapies available for the treatment of metastatic UM, hence it is a clinical area of urgent unmet need. Here, the clinical relevance and therapeutic potential of cysteinyl leukotriene receptors (CysLT1 and CysLT2) in UM was evaluated. High expression of CYSLTR1 or CYSLTR2 transcripts is significantly associated with poor disease-free survival and poor overall survival in UM patients. Digital pathology analysis identified that high expression of CysLT1 in primary UM is associated with reduced disease-specific survival (p = 0.012; HR 2.76; 95% CI 1.21–6.3) and overall survival (p = 0.011; HR 1.46; 95% CI 0.67–3.17). High CysLT1 expression shows a statistically significant (p = 0.041) correlation with ciliary body involvement, a poor prognostic indicator in UM. Small molecule drugs targeting CysLT1 were vastly superior at exerting anti-cancer phenotypes in UM cell lines and zebrafish xenografts than drugs targeting CysLT2. Quininib, a selective CysLT1 antagonist, significantly inhibits survival (p < 0.0001), long-term proliferation (p < 0.0001), and oxidative phosphorylation (p < 0.001), but not glycolysis, in primary and metastatic UM cell lines. Quininib exerts opposing effects on the secretion of inflammatory markers in primary versus metastatic UM cell lines. Quininib significantly downregulated IL-2 and IL-6 in Mel285 cells (p < 0.05) but significantly upregulated IL-10, IL-1β, IL-2 (p < 0.0001), IL-13, IL-8 (p < 0.001), IL-12p70 and IL-6 (p < 0.05) in OMM2.5 cells. Finally, quininib significantly inhibits tumour growth in orthotopic zebrafish xenograft models of UM. These preclinical data suggest that antagonism of CysLT1, but not CysLT2, may be of therapeutic interest in the treatment of UM.

show abstract

Section: Discussionmentioning

confidence: 99%

High Cysteinyl Leukotriene Receptor 1 Expression Correlates with Poor Survival of Uveal Melanoma Patients and Cognate Antagonist Drugs Modulate the Growth, Cancer Secretome, and Metabolism of Uveal Melanoma Cells

Slater

Heeran

García-Mulero

et al. 2020

Cancers

View full text Add to dashboard Cite

show abstract

“…Colon cancer is one of the leading causes of cancer-related deaths worldwide, and the incidence has been rising in recent years ( 25 – 27 ). The occurrence and development of colon cancer have been related to many factors, including living habits, genes and many other factors ( 28 – 30 ).…”

Section: Discussionmentioning

confidence: 99%

Long non-coding RNA LINC00261 sensitizes human colon cancer cells to cisplatin therapy

Wang

Yang

et al. 2018

Braz J Med Biol Res

View full text Add to dashboard Cite

Colon cancer is one of the most common digestive tumors. The present study aimed to explore the functional role, as well as the underlying mechanism of long non-coding RNA LINC00261 in colon cancer. Expression of LINC00261 was analyzed in colon cancer cell lines and human normal cell lines. Acquired resistance cell lines were then built and the acquired resistance efficiency was detected by evaluating cell viability. Thereafter, the effects of LINC00261 overexpression on cisplatin-resistant colon cancer cells were measured, as well as cell apoptosis, viability, migration, and invasion. Subsequently, we investigated the interaction of LINC00261 and β-catenin. The results showed that the LINC00261 gene was down-regulated in colon cancer cell lines and tissues, and in cisplatin-resistant cells. LINC00261 overexpression might relieve cisplatin resistance of colon cancer cells via promoting cell apoptosis, and inhibiting cell viability, migration, and invasion. Moreover, LINC00261 might down-regulate nuclear β-catenin through restraining β-catenin from cytoplasm into nuclei or it could also promote β-catenin degradation and inhibit activation of Wnt pathway. Finally, LINC00261 reduced cisplatin resistance of colon cancer in vivo and enhanced the anti-colon cancer effect of cisplatin through reducing tumor volume and weight.

show abstract

“…We have previously shown that CRC patients with low-CysLT 2 R and/or low-15-PGDH expression have a poor prognosis 12,20 . In this study, we noted that patients with high-GLI1 expression coupled with either low-CysLT 2 R expression or low-15-PGDH expression had poorer prognoses than patients with either low-GLI1 and low-15-PGDH expression or low-GLI1 and low-CysLT 2 R expression ( Fig.…”

Section: Gli1 Expression Is Negatively Correlated With Cyslt2r 15-pgmentioning

confidence: 99%

“…We determined whether Hh-GLI signalling was involved in the LTC 4 -induced 15-PGDH-promoted differentiation of CC cells 20 . Interestingly, LTC 4 stimulation significantly downregulated GLI1 expression at both the mRNA and protein levels compared with unstimulated HT-29 and Caco-2 cells (Fig.…”

Section: Ltc4-induced 15-pgdh Downregulates Gli1 In Colon Cancer Cellsmentioning

confidence: 99%

“…15-PGDH is abundantly expressed in normal colon mucosa, but its expression is lost in CRC cells 16,17 , leading to disease progression. Recently, researchers have explored the efficacy of 15-PGDH as a potential antitumour agent against colon cancer [18][19][20][21] . In a recent study, we established that 15-PGDH is induced by LTC 4 via CysLT 2 R signalling by phosphorylating c-Jun N-terminal kinase and AP-1 to induce 15-PGDH promoter activity and further guide colon cancer cells toward redifferentiation 20 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Tumour suppressor 15-hydroxyprostaglandin dehydrogenase induces differentiation in colon cancer via GLI1 inhibition

et al. 2020

Self Cite

View full text Add to dashboard Cite

Inflammation is an established risk factor for colorectal cancer. We and others have shown that colorectal cancer patients with elevated cysteinyl leukotriene receptor 2 (CysLT 2 R) and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) levels exhibit good prognoses. However, both CysLT 2 R and 15-PGDH, which act as tumour suppressors, are often suppressed in colorectal cancer. We previously reported that leukotriene C 4 (LTC 4)-induced differentiation in colon cancer via CysLT 2 R signalling. Here, we investigated the involvement of Hedgehog (Hh)-GLI1 signalling, which is often hyperactivated in colorectal cancer. We found that the majority of colorectal cancer patients had high-GLI1 expression, which was negatively correlated with CysLT 2 R, 15-PGDH, and Mucin-2 and overall survival compared with the low-GLI1 group. LTC 4-induced 15-PGDH downregulated both the mRNA and protein expression of GLI1 in a protein kinase A (PKA)-dependent manner. Interestingly, the LTC 4-induced increase in differentiation markers and reduction in Wnt targets remained unaltered in GLI1-knockdown cells. The restoration of GLI1 in 15-PGDH-knockdown cells did not ameliorate the LTC 4-induced effects, indicating the importance of both 15-PGDH and GLI1. LTC 4-mediated reduction in the DCLK1 and LGR5 stemness markers in colonospheres was abolished in cells lacking 15-PGDH or GLI1. Both DCLK1 and LGR5 were highly increased in tumour tissue compared with the matched controls. Reduced Mucin-2 levels were observed both in zebrafish xenografts with GLI1-knockdown cells and in the cysltr2 −/− colitis-associated colon cancer (CAC) mouse model. Furthermore, GLI1 expression was positively correlated with stemness and negatively correlated with differentiation in CRC patients when comparing tumour and mucosal tissues. In conclusion, restoring 15-PGDH expression via CysLT 2 R activation might benefit colorectal cancer patients.

show abstract

A potential anti-tumor effect of leukotriene C4 through the induction of 15-hydroxyprostaglandin dehydrogenase expression in colon cancer cells

Cited by 23 publications

References 32 publications

High Cysteinyl Leukotriene Receptor 1 Expression Correlates with Poor Survival of Uveal Melanoma Patients and Cognate Antagonist Drugs Modulate the Growth, Cancer Secretome, and Metabolism of Uveal Melanoma Cells

High Cysteinyl Leukotriene Receptor 1 Expression Correlates with Poor Survival of Uveal Melanoma Patients and Cognate Antagonist Drugs Modulate the Growth, Cancer Secretome, and Metabolism of Uveal Melanoma Cells

Long non-coding RNA LINC00261 sensitizes human colon cancer cells to cisplatin therapy

Tumour suppressor 15-hydroxyprostaglandin dehydrogenase induces differentiation in colon cancer via GLI1 inhibition

Contact Info

Product

Resources

About