Inhibition of 15-PGDH causes Kras-driven tumor expansion through prostaglandin E2-ALDH1 signaling in the pancreas
Inhibition of 15-PGDH causes Kras-driven tumor expansion through prostaglandin E2-ALDH1 signaling in the pancreas
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DOI：
10.1038/s41388-018-0510-y
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发表时间：
2019-02-21
期刊：
影响因子：
8
通讯作者：
Ishimoto, Takatsugu
中科院分区：
文献类型：
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作者：
Arima, Kota;Ohmuraya, Masaki;Ishimoto, Takatsugu
前列腺素E_2(PGE(2))在慢性炎症过程中的积聚与几种癌症的进展有关。环氧合酶是前列腺素E(2)的关键合成酶，而降解酶15-羟基前列腺素脱氢酶(15-PGDH)近年来备受关注。我们通过15-前列腺素脱氢酶下调胰腺导管腺癌(PDAC)进展的分子机制进行了研究。在这里，我们发现15-PGDH的表达与ALDH1呈负相关，ALDH1是一种重要的癌症干细胞相关标记物，表明人类预后不良。此外，我们还证明了药物抑制15-PGDH增强了CYP26A1的表达，导致人PDAC细胞和Kras(LSL-G12D/+)、Ptfla(Cre/+)(KC)小鼠的肿瘤细胞中ALDH1阳性亚群的扩张和全反式维甲酸(ATRA)的耗竭。此外，KC小鼠15-PGDH基因缺失导致胰腺中PGE(2)蓄积和ATRA耗竭，导致PDAC中Aldh1和Ki-67水平升高。最后，全反式维甲酸替代抑制15-前列腺素脱氢酶抑制KC小鼠肿瘤进展，全反式维甲酸治疗减弱15-前列腺素脱氢酶(-/-)KC小鼠胰腺肿瘤细胞Aldh1活性。这些发现提供了证据，证明15-PGDH抑制通过胰腺ATRA耗竭增强KRAS驱动的肿瘤进展。因此，ATRA替代治疗PDAC可能是一种潜在的策略。
The accumulation of prostaglandin E2 (PGE(2)) during chronic inflammation has been implicated in the progression of several cancers. Cyclooxygenase is the key synthesizing enzyme of PGE(2), although the degradation enzyme 15-ydroxyprostaglandin dehydrogenase (15-PGDH) has received considerable attention recently. We investigated the molecular mechanisms of pancreatic ductal adenocarcinoma (PDAC) progression via 15-PGDH downregulation. Here, we found that 15-PGDH expression was inversely correlated with ALDH1, an important cancer stem cell-associated marker indicative of poor prognosis in humans. Moreover, we demonstrated that pharmacological inhibition of 15-PGDH enhanced CYP26A1 expression, leading to depletion of all-trans retinoic acid (ATRA) and expansion of the ALDH1-positive subset in both human PDAC cells and tumor cells of Kras(LSL-G12D/+); Ptfla(Cre/+) (KC) mice. Furthermore, genetic deletion of 15-Pgdh in KC mice showed PGE(2) accumulation and ATRA depletion in the pancreas, resulting in PDAC with high levels of Aldh1 and Ki-67. Finally, ATRA replacement suppressed 15-PGDH inhibition-induced tumor progression in KC mice, and ATRA treatment attenuated Aldh1 activity in tumor cells isolated from the pancreas of 15-Pgdh(-/-) KC mice. These findings provide evidence that 15-PGDH inhibition enhances KRAS-driven tumor progression via ATRA depletion in the pancreas. Therefore, ATRA replacement could be a potential strategy for PDAC treatment.