Aldo-keto reductase 1C3 is overexpressed in skin squamous cell carcinoma (SCC) and affects SCC growth via prostaglandin metabolism.
Aldo-keto reductase 1C3 is overexpressed in skin squamous cell carcinoma (SCC) and affects SCC growth via prostaglandin metabolism.
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DOI：
10.1111/exd.12468
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发表时间：
2014-08
影响因子：
3.6
通讯作者：
Pentland AP
中科院分区：
文献类型：
--
作者：
Mantel A;Carpenter-Mendini A;VanBuskirk J;Pentland AP
醛酮还原酶1C 3（AKR 1C 3）是一种参与代谢前列腺素（PGs）和性激素的酶。它将PGD 2代谢为9α11β-PGF 2，将PGD 2自发转化为PPARγ激动剂15-脱氧-Delta-12，14-前列腺素J2（15 d-PGJ 2）。AKR 1C 3在多种恶性肿瘤中过表达，提示其具有促肿瘤功能。这项工作研究了AKR 1C 3在人类非黑色素瘤皮肤癌中的表达，揭示了鳞状细胞癌（SCC）中的过度表达。然后使用3种SCC细胞系评估AKR 1C 3过表达的影响。在所有SCC细胞系中检测到AKR 1C 3，并且其表达响应于其底物PGD 2而上调。虽然通过siRNA减弱SCC细胞中AKR 1C 3的表达并不影响生长，但用PGD 2及其脱水代谢产物15 d-PGJ 2处理以PPARγ依赖性方式降低SCC增殖。此外，用PPARγ激动剂吡格列酮治疗显著抑制SCC增殖。最后，我们产生了稳定过表达AKR 1C 3的SCC细胞系（SCC-AKR 1C 3）。SCC-AKR 1C 3将PGD 2代谢为9α11β-PGF 2的速度比亲本细胞系快12倍，并且受到PGD 2介导的抗增殖作用的保护。这项研究表明，PGD 2及其代谢产物15 d-PGJ 2以PPARγ依赖性方式减弱SCC增殖，因此，通过激动剂如吡格列酮激活PPARγ可能使SCC高危人群受益。
Aldo-keto reductase 1C3 (AKR1C3) is an enzyme involved in metabolizing prostaglandins (PGs) and sex hormones. It metabolizes PGD2 to 9α11β-PGF2, diverting the spontaneous conversion of PGD2 to the PPARγ agonist, 15-Deoxy-Delta-12,14-prostaglandin J2 (15d-PGJ2). AKR1C3 is overexpressed in various malignancies, suggesting a tumor promoting function. This work investigates AKR1C3 expression in human non-melanoma skin cancers, revealing overexpression in squamous cell carcinoma (SCC). Effects of AKR1C3 overexpression were then evaluated using 3 SCC cell lines. AKR1C3 was detected in all SCC cell lines and its expression was upregulated in response to its substrate, PGD2. Although attenuating AKR1C3 expression in SCC cells by siRNA did not affect growth, treatment with PGD2 and its dehydration metabolite, 15d-PGJ2, decreased SCC proliferation in a PPARγ-dependent manner. In addition, treatment with the PPARγ agonist pioglitazone profoundly inhibited SCC proliferation. Finally, we generated an SCC cell line that stably overexpressed AKR1C3 (SCC-AKR1C3). SCC-AKR1C3 metabolized PGD2 to 9α11β-PGF2 12 fold faster than the parent cell line and was protected from the anti-proliferative effect mediated by PGD2. This work suggests that PGD2 and its metabolite 15d-PGJ2 attenuate SCC proliferation in a PPARγ-dependent manner, therefore activation of PPARγ by agonists such as Pioglitazone may benefit those at high risk of SCC.
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影响因子：
2
作者：
Costa, Nadia Lago;Oton-Leite, Angelica Ferreira;Batista, Aline Carvalho
通讯作者：
Batista, Aline Carvalho
影响因子：
64.5
作者：
RHEINWALD, JG;BECKETT, MA
通讯作者：
BECKETT, MA
影响因子：
4.7
作者：
PARKINSON, EK;PERA, MF;GORMAN, PA
通讯作者：
GORMAN, PA
影响因子：
4.1
作者：
Penning, TM;Burczynski, ME;Ratnam, K
通讯作者：
Ratnam, K
影响因子：
2.9
作者：
Komoto, J;Yamada, T;Takusagawa, F
通讯作者：
Takusagawa, F