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  • ET expression occurs in many carcinomas including those


    ET-1 expression occurs in many carcinomas, including those arising in the kidney [38], prostate [7], ovary [5] endometrium [39], melanocyte [40], and central nervous system [41], [42], among others [43]. The endothelin axis expression in RCC appears to be dependent upon the tumor subtype [38]. In several carcinomas, ET-1 induces proliferation through the ETA receptor. Concomitantly, decreased ETB expression has been implicated in the pathogenesis of prostate [44], [45] and ovarian cancer [5]. The transcriptional regulatory region of the ETB receptor gene (EDNRB) contains a 5′ CpG island [21], and in human prostate cancer this region is commonly (70%) methylated [45], suggesting ETB downregulation occurs through suppression of transcription. ET-1, acting through ETA, has been shown to promote cell survival in benign stromal cell populations exposed to paclitaxel [46], [47]. Given the expression of ET-1 and the ET receptors in the normal as well as the cancerous kidney, it was our hypothesis the ET axis functions as a survival pathway in RCC. Therefore, we studied ET axis expression in RCC, and demonstrated that ET-1, acting through ETA and the downstream PI-3 kinase pathway, promotes cell survival.
    Method and materials
    Discussion Given the potential role of ET-1 in tumorigenesis and the promise shown by select endothelin receptor antagonists in treating cancer, we investigated ET-1 signaling in RCC. All six RCC cell lines studied secreted levels of ET-1 at concentrations high enough to potentially activate receptors in an autocrine fashion. ETA expression was observed in all six cell lines and high affinity binding of ET-1 was evident in five of those lines. Furthermore, we demonstrated that ET-1 signaling in RCC induces protection from apoptosis through inducing the PI3-kinase pathway and activating Akt. Taken together, these data indicate that the survival effect of ET-1 is propagated via the ETA receptor. Identification of the profile of the ET signaling axis in RCC may promote new insight into potential therapeutic interventions. In a fashion similar to prostate [45] and ym express cancers [51], EDNRB promoter methylation was frequently observed in RCC lines and human renal tumors. Hypermethylation of the 5′ CpG island in the regulatory region of EDNRB likely results in inhibition of ETB expression and perhaps in the clonal expansion of malignant cells. The finding of EDNRB methylation in histologically normal renal tissues from kidneys bearing tumors was unexpected, given our previous work that demonstrated no EDNRB methylation in any normal tissue studied. Although several cell types are present in the histologically benign tissue adjacent to the tumors, it is possible that ETB promoter methylation occurs as a premalignant, epigenetic alteration in some cells prior to transformation. As the receptor of ligand clearance and inhibition of ET-1 secretion, ETB inactivation can increase local ET-1 concentrations. The loss of ETB expression may contribute to carcinogenesis in the kidney through unregulated ETA activation by autocrine or paracrine ET-1. ET-1 demonstrates diverse affects in the kidney including contraction, cell proliferation, extracellular matrix formation as well as sodium and water excretion. Most renal cell types produce ET and also express ETA and/or ETB receptors [9], [31], [52]. Although both ETA and ETB receptors are coupled to many of the same signaling molecules, the ETB receptor activation can uniquely mediate divergent responses, such as vasodilation through nitric oxide production [24] and apoptosis [25], [53], in opposition to the vasoconstriction [3] and cell survival [54], [53] response of ETA signaling. ET-1 is thought to mediate short-term actions such as contraction and secretion by rapid calcium mobilization [55], [56], [57] and exert long-term nuclear signaling leading to gene expression [58]. Endothelin receptors belong to a family of G protein-coupled receptors that can activate multiple types of effectors. Evidence for ETB receptor negative growth effects have been demonstrated in melanoma [25] and smooth muscle cells [27]. Mitogenic signals induced by ET-1 through the ETA receptor may be transduced through two independent pathways [59]. The first signaling cascade is transduced ym express through phospholipase C/D induced formation of diaclyglycerol and protein kinase C (PKC) activation. This pathway often triggers Ras activation through tyrosine phosphorylation of Shc and association of Grb2 and Sos1which then activates MAPK. The other pathway involves PI3-kinase activation to trigger increases in cellular levels of D-3 phosphorylated phosphoinositides that act as second messengers.