Endothelins and their receptors in cancer: Identification of therapeutic targets

Wang, Rong; Dashwood, Roderick H.

doi:10.1016/j.phrs.2011.01.002

Cited by 36 publications

(29 citation statements)

References 67 publications

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“…Despite the growing interest in the ET axis and its role in cancer,1–3 most attention to date has focused on ET‐1 and its receptors, with surprisingly little information on ET‐2 and ET‐3. In fact, there is a significant gap in our general understanding of the lesser studied ET isoforms and their functions in normal physiology and pathophysiology, especially in the case of ET‐2.…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

“…There is growing interest in the endothelin (ET) axis and its dysregulation in cancer development 1–3. This “axis” comprises the 21‐amino acid peptides ET‐1, ET‐2 and ET‐3, the G‐protein‐coupled receptors ET A R and ET B R and upstream processing enzymes such as ET converting enzyme 1 1–3. ET‐1 is by far the best characterized isoform, being a potent vasoconstrictor with key roles in normal physiology and in various pathophysiological conditions 4, 5.…”

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confidence: 99%

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Epigenetic inactivation of endothelin‐2 and endothelin‐3 in colon cancer

Wang

Löhr

Fischer

et al. 2012

Intl Journal of Cancer

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Endothelin-1 (ET-1) and its receptors are overexpressed in human cancers, but much less is known about the roles of ET-2 and ET-3 in cancer etiology. We sought to examine human and rat colon tumors for dysregulation of ET-2 and ET3 expression, and determine the underlying mechanisms. Human primary colon cancers and carcinogen-induced rat colon tumors were subjected to real-time RT-PCR, immunoblotting, and immunohistochemistry; EDN2 and EDN3 genes were examined by methylation-specific PCR, bisulfite sequencing, and pyrosequencing; and forced expression of ET-2 and ET-3 was conducted in human colon cancer cells followed by real-time cell migration and invasion assays. Rat and human colon tumors had markedly reduced expression of ET-2 and ET-3 mRNA and protein compared with matched controls. Mechanistic studies revealed hypermethylation of EDN2 and EDN3 genes in human primary colon cancers, and in a panel of human colon cancer cell lines. Forced expression of ET-2 and ET-3 attenuated significantly the migration and invasion of human colon cancer cells. We conclude that epigenetic inactivation of ET-2 and ET-3 occurs frequently in both rat and human colon cancers. Current therapeutic strategies target overexpressed members of the ET axis via small molecule inhibitors and receptor antagonists, but this work supports a complementary approach based on the re-expression of ET-2 and ET-3 as natural antagonists of ET-1 in colon cancer.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Epigenetic inactivation of endothelin‐2 and endothelin‐3 in colon cancer

Wang

Löhr

Fischer

et al. 2012

Intl Journal of Cancer

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“…134 As well as mediating peritubular contractility and sperm passage through the epididymal lumen, endothelins and their receptors (ER) are associated with cancer. 135 ER-A is involved in cell proliferation, migration, invasion and angiogenesis, and ER-B in countering tumour progression by promoting apoptosis and binding ET-1. 136 Endothelin-1 and these receptors are present in the human epididymal epithelium and peritubular muscle, respectively.…”

Section: Rarity Of Epididymal Cancermentioning

confidence: 99%

Why are epididymal tumours so rare?

Yeung¹,

Wang²,

Cooper³

2012

Asian J Androl

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Epididymal tumour incidence is at most 0.03% of all male cancers. It is an enigma why the human epididymis does not often succumb to cancer, when it expresses markers of stem and cancer cells, and constitutively expresses oncogenes, pro-proliferative and pro-angiogenic factors that allow tumour cells to escape immunosurveillance in cancer-prone tissues. The privileged position of the human epididymis in evading tumourigenicity is reflected in transgenic mouse models in which induction of tumours in other organs is not accompanied by epididymal neoplasia. The epididymis appears to: (i) prevent tumour initiation (it probably lacks stem cells and has strong anti-oxidative mechanisms, active tumour suppressors and inactive oncogene products); (ii) foster tumour monitoring and destruction (by strong immuno-surveillance and -eradication, and cellular senescence); (iii) avert proliferation and angiogenesis (with persistent tight junctions, the presence of anti-angiogenic factors and misplaced pro-angiogenic factors), which together (iv) promote dormancy and restrict dividing cells to hyperplasia. Epididymal cells may be rendered non-responsive to oncogenic stimuli by the constitutive expression of factors generally inducible in tumours, and resistant to the normal epididymal environment, which mimics that of a tumour niche promoting tumour growth. The threshold for tumour initiation may thus be higher in the epididymis than in other organs. Several anti-tumour mechanisms are those that maintain spermatozoa quiescent and immunologically silent, so the low incidence of cancer in the epididymis may be a consequence of its role in sperm maturation and storage. Understanding these mechanisms may throw light on cancer prevention and therapy in general.

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“…ET-1 is metabolized by neutral endopeptidase from a 212 amino acid prepro-ET-1 to big-ET-1 containing 38 amino acids. Big ET-1 is subsequently metabolized by endothelin converting enzyme (ECE-1) to ET-1 [41]. ET-1 is present in many human cancer cell lines derived breast, colon, lung, prostate and stomach cancer [1, 22, 31] ET-1 is overexpressed in breast, colorectal, lung and ovarian tumors [4, 7].…”

Section: Introductionmentioning

confidence: 99%

Endothelin causes transactivation of the EGFR and HER2 in non-small cell lung cancer cells

et al. 2017

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Endothelin (ET)-1 is an important peptide in cancer progression stimulating cellular proliferation, tumor angiogenesis and metastasis. ET-1 binds with high affinity to the ETA receptor (R) and ETBR on cancer cells. High levels of tumor ET-1 and ETAR are associated with poor survival of lung cancer patients. Here the effects of ET-1 on epidermal growth factor (EGF)R and HER2 transactivation were investigated using non-small cell lung cancer (NSCLC) cells. ETAR mRNA was present in all 10 NSCLC cell lines examined. Addition of ET-1 to NCI-H838 or H1975 cells increased EGFR, HER2 and ERK tyrosine phosphorylation within 2 min. The increase in EGFR and HER2 transactivation caused by ET-1 addition to NSCLC cells was inhibited by lapatinib (EGFR and HER2 tyrosine kinase inhibitor (TKI)), gefitinib (EGFR TKI), ZD4054 or BQ-123 (ETAR antagonist), GM6001 (matrix metalloprotease inhibitor), PP2 (Src inhibitor) or Tiron (superoxide scavenger). ET-1 addition to NSCLC cells increased cytosolic Ca2+ and reactive oxygen species. ET-1 increased NSCLC clonal growth, whereas BQ123, ZD4054, lapatinib or gefitinib inhibited proliferation. The results indicate that ET-1 may regulate NSCLC cellular proliferation in an EGFR-and HER2-dependent manner.

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Endothelins and their receptors in cancer: Identification of therapeutic targets

Cited by 36 publications

References 67 publications

Epigenetic inactivation of endothelin‐2 and endothelin‐3 in colon cancer

Epigenetic inactivation of endothelin‐2 and endothelin‐3 in colon cancer

Why are epididymal tumours so rare?

Endothelin causes transactivation of the EGFR and HER2 in non-small cell lung cancer cells

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