Adrenomedullin inhibits hypoxic cell death by upregulation of Bcl-2 in endometrial cancer cells: a possible promotion mechanism for tumour growth
Adrenomedullin inhibits hypoxic cell death by upregulation of Bcl-2 in endometrial cancer cells: a possible promotion mechanism for tumour growth
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DOI：
10.1038/sj.onc.1204422
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发表时间：
2001-05-24
期刊：
影响因子：
8
通讯作者：
Bicknell, R
中科院分区：
文献类型：
--
作者：
Oehler, MK;Norbury, C;Bicknell, R
缺氧区域是实体瘤的共同特征，当肿瘤细胞暴露于缺氧应激时，启动一系列基因的转录。血管生成因子肾上腺髓质素（ADM）是一种缺氧调节基因，ADM通过G蛋白偶联受体降钙素受体样受体（CRLR）发挥作用，其特异性由受体相关修饰蛋白2（RAMP 2）赋予。ADM处理或稳定转染的过表达ADM的石川细胞首次显示出对缺氧诱导的细胞凋亡的抗性增加，这些细胞还显示出癌蛋白Bcl-2的上调，当瞬时转染到石川细胞中时，Bcl-2对缺氧细胞死亡具有保护作用。由于石川细胞表达假定的ADM受体CRLR-RAMP 2，ADM的产生和分泌以及Bcl-2的连续上调可以建立自分泌/旁分泌机制，拯救恶性细胞免于缺氧细胞死亡。这些结果，与我们以前的研究结果，ADM是一种血管生成因子，它是上调的非甾体抗雌激素他莫昔芬（TAM）在子宫内膜细胞，牵连这种肽作为肿瘤生长的促进剂和可能的抗癌策略的目标。Oncogene（2001）20，2937-2945.
Regions of hypoxia are a common feature of solid tumours, When tumour cells are exposed to hypoxic stress, transcription of a battery of genes is initiated. The angiogenic factor adrenomedullin (ADM) is a hypoxia regulated gene, ADM is thought to act through the G protein-coupled receptor calcitonin receptor-like receptor (CRLR), with specificity being conferred by the receptor associated modifying protein 2 (RAMP2), Here we report for the! first time that ADM treated or stably transfected Ishikawa cells overexpressing ADM show increased resistance to hypoxia induced apoptosis, These cells also show an upregulation of the oncoprotein Bcl-2, which is protective against hypoxic cell death when transiently transfected into Ishikawa cells. Since Ishikawa cells express the putative ADM-receptor CRLR-RAMP2 the production and secretion of ADM with the consecutive upregulation of Bcl-2 could establish an autocrine/paracrine mechanism rescuing malignant cells from hypoxic cell death. These results, taken together with our previous findings that ADM is an angiogenic factor which is upregulated by the nonsteroidal antiestrogen tamoxifen (TAM) in endometrial cells, implicate this peptide as a promoter of tumour growth and a possible target for anticancer strategies. Oncogene (2001) 20, 2937-2945.