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Cysteinyl Leukotrienes and Their Receptors: Potential Roles in Endothelial Function and Cancer

Duah, Ernest
http://orcid.org/0000-0002-8510-4276
http://rave.ohiolink.edu/etdc/view?acc_num=akron1469466659

Abstract Details

2016, Doctor of Philosophy, University of Akron, Chemistry.
Cysteinyl leukotrienes (cys-LTs), LTC4, LTD4, and LTE4 are potent inflammatory lipid mediators that act through two distinct G-protein-coupled receptors, CysLT1R and CysLT2R. Cys-LTs and their receptors have been implicated in a number of diseases including atherosclerosis and cancer. However, the molecular mechanism by which cys-LTs modulate their effects is not fully understood. In the first part of this dissertation, we demonstrate that cys-LTs (LTC4 and LTD4) induce robust calcium influx in human umbilical vein endothelial cells (HUVECs) through CysLT2R, but not CysLT1R. Further, cys-LT treatment induced endothelial cell (EC) contraction, leading to monolayer disruption via CysLT2R/ROCK-dependent pathway. Additionally, stimulation with cys-LTs potentiated TNFa-induced VCAM-1 expression and leukocyte recruitment to ECs through CysLT2R. Taken together, these results suggest that cys-LTs induce endothelial dysfunction via CysLT2R/ROCK dependent pathways. Endothelial dysfunction can significantly contribute to cardiovascular diseases such as atherosclerosis and aberrant angiogenesis. Angiogenesis, the formation of new blood vessels from existing ones is required for invasive tumor growth and metastasis and constitutes an important point in the control of cancer progression. Cysteinyl leukotriene receptors (CysLTR) have been shown to be upregulated in a number of cancers. However, the specific role played by CysLTR during tumor growth and progression is not known. Therefore, in the second part of this dissertation, using Lewis lung carcinoma (LLC) syngeneic tumor model, we demonstrate for the first time that cys-LTs can promote angiogenesis in vitro and in vivo. Further, employing CysLTR knock out (KO) mice (Cysltr1-/-, Cysltr2-/-), we established that CysLT2R promotes subcutaneous tumor growth, angiogenesis and lung metastasis. Pharmacological blockage of CysLT2R with BaycysLT2 (Bay) resulted in less tumor angiogenesis, increased vascular normalization and attenuated metastasis to lung, similar to the results obtained using KO animals. Our results demonstrate that blocking CysLT2R via Bay has a potential to normalize vessels. Combination treatment with Bay and Cisplatin resulted in a better anti-tumor effect compared to Bay or cisplatin alone. In conclusion, these findings provide evidence that, CysLT2R plays a significant role in tumor angiogenesis and vascular integrity leading to tumor growth and metastasis. Targeting CysLT2R could produce beneficial effects in treating cancer and many other angiogenesis-dependent diseases.
Sailaja Paruchuri (Advisor)
137 p.
Biochemistry; Cellular Biology
Cysteinyl leukotrienes, tumor angiogenesis, endothelial dysfunction, cancer

Recommended Citations

Citations

  • Duah, E. (2016). Cysteinyl Leukotrienes and Their Receptors: Potential Roles in Endothelial Function and Cancer [Doctoral dissertation, University of Akron]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=akron1469466659

    APA Style (7th edition)

  • Duah, Ernest. Cysteinyl Leukotrienes and Their Receptors: Potential Roles in Endothelial Function and Cancer. 2016. University of Akron, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=akron1469466659.

    MLA Style (8th edition)

  • Duah, Ernest. "Cysteinyl Leukotrienes and Their Receptors: Potential Roles in Endothelial Function and Cancer." Doctoral dissertation, University of Akron, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=akron1469466659

    Chicago Manual of Style (17th edition)

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This open access ETD is published by University of Akron and OhioLINK.