Suppression of prostate tumor cell growth by stromal cell prostaglandin D synthase-derived products
Suppression of prostate tumor cell growth by stromal cell prostaglandin D synthase-derived products
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DOI：
10.1158/0008-5472.can-04-4439
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发表时间：
2005-07-15
期刊：
影响因子：
11.2
通讯作者：
Menter, DG
中科院分区：
文献类型：
--
作者：
Kim, J;Yang, PY;Menter, DG
基质-上皮相互作用和由这些相互作用产生的生物活性分子维持组织稳态并影响癌发生。由前列腺素酶产生并由前列腺分泌到精浆中的生物活性前列腺素被认为支持生殖，但其对癌症形成的内源性影响尚未得到解决。迄今为止，还没有研究检测正常前列腺基质细胞中前列腺素酶的产生或前列腺素代谢。我们的研究结果表明，正常前列腺基质细胞产生的脂质运载蛋白型前列腺素D合成酶（L-PGDS）和前列腺素D-2（PGD（2））代谢产物通过过氧化物酶体增殖物激活受体γ（PPAR γ）依赖性机制抑制肿瘤细胞生长。基质细胞L-PGDS的酶促产物包括高水平的PGD 2和15-脱氧-Delta（12，14）-PGD（2），但低水平的15-脱氧-Delta（12，14）-前列腺素J（2）。这些PGD（2）代谢物激活了PPAR γ配体结合域和过氧化物酶体增殖物反应元件报告系统。因此，前列腺微环境中PGD（2）代谢产物对表达PPAR γ的肿瘤细胞的生长抑制可能是肿瘤抑制的内源性机制，可能导致该疾病的无痛性和长潜伏期。
Stromal-epithelial interactions and the bioactive molecules produced by these interactions maintain tissue homeostasis and influence carcinogenesis. Bioactive prostaglandins produced by prostaglandin synthases and secreted by the prostate into seminal plasma are thought to support reproduction, but their endogenous effects on cancer formation remain unresolved. No studies to date have examined prostaglandin enzyme production or prostaglandin metabolism in normal prostate stromal cells. Our results show that lipocalin-type prostaglandin D synthase (L-PGDS) and prostaglandin D-2 (PGD(2)) metabolites produced by normal prostate stromal cells inhibited tumor cell growth through a peroxisome proliferator-activated receptor gamma (PPAR gamma)-dependent mechanism. Enzymatic products of stromal cell L-PGDS included high levels of PGD2 and 15-deoxy-Delta(12,14) -PGD(2) but low levels of 15-deoxy-Delta(12,14) -prostaglandin J(2). These PGD(2) metabolites activated the PPAR gamma ligand-binding domain and the peroxisome proliferator response element reporter systems. Thus, growth suppression of PPAR gamma-expressing tumor cells by PGD(2) metabolites in the prostate microenvironment is likely to be an endogenous mechanism involved in tumor suppression that potentially contributes to the indolence and long latency period of this disease.