Endothelin-1 promotes cell survival in renal cell carcinoma through the ETA receptor

Beth R. Pflug, Hong Zheng, Michael S. Udan, Jason M. D'Antonio, Fray F. Marshall, James D. Brooks, Joel B. Nelson

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

Endothelin-1 (ET-1) is a potent vasoconstrictor that has been shown to significantly impact many benign and malignant tissues by signaling through its two cognate receptors: ETA and ETB. As ET-1 has a role in both normal and diseased kidney, we initiated studies to investigate endothelin axis expression and function in renal cell carcinoma (RCC). In this study, relatively high levels of ET-1 were detected in all six human RCC cell lines investigated. RT-PCR and Southern analyses revealed that all six RCC cell lines expressed ETA receptor mRNA, while 3/6 cell lines also expressed ETB mRNA. High affinity ET-1 binding occurred in all but one RCC cell line and quantitative RT-PCR demonstrated ETA mRNA expression in all six cell lines. Methylation of the ETB promoter (EDNRB) in 4/6 RCC cell lines was observed, suggesting a mechanism for repressed ETB expression. Moreover, methylation occurred in 32/48 of renal tumors and in 27/55 of histologically normal adjacent tissue samples studied, while no methylation was evident in any normal tissue isolated from nephrectomy or at autopsy. Functionally, ET-1 significantly inhibited paclitaxel-induced apoptosis in RCC cells through binding ETA with the ET-1 signaling mediated via the PI3-kinase/Akt pathway. Collectively, these data support the therapeutic targeting of the ETA receptor as a novel treatment strategy for RCC.

Original languageEnglish (US)
Pages (from-to)139-148
Number of pages10
JournalCancer Letters
Volume246
Issue number1-2
DOIs
StatePublished - Feb 8 2007
Externally publishedYes

Keywords

  • Cell survival
  • Endothelin receptors
  • Endothelin-1
  • Renal cell carcinoma

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Pflug, B. R., Zheng, H., Udan, M. S., D'Antonio, J. M., Marshall, F. F., Brooks, J. D., & Nelson, J. B. (2007). Endothelin-1 promotes cell survival in renal cell carcinoma through the ETA receptor. Cancer Letters, 246(1-2), 139-148. https://doi.org/10.1016/j.canlet.2006.02.007