Loss of 15-Hydroxyprostaglandin Dehydrogenase Expression Contributes to Bladder Cancer Progression

Abstract

Prostaglandin E2 , which is known to contribute to cancer progression, is inactivated by the catabolic enzyme, 15-hydroxyprostaglandin dehydrogenase (PGDH), which has tumor-suppressor activity in lung, colon, breast, and gastric cancers. Therefore, we evaluated the expression of PGDH in human bladder cancer tissue specimens and cell lines. Immunoperoxidase staining of bladder cancer tissues demonstrated that (1) PGDH is highly expressed by normal urothelial cells but (2) reduced in many low stage (Ta/Tis) bladder cancers, and (3) PGDH is completely lost in most invasive bladder cancers. Of eight cancer cell lines tested, only two relatively well-differentiated bladder cancer cell lines, RT4 and UM-UC9, expressed PGDH. Moreover, inhibition of PGDH expression in well-differentiated RT4 cells using small inhibitory RNA or short hairpin RNA resulted in a more aggressive phenotype with increased motility and anchorage-independent growth. Additionally, PGDH knockdown affected prostaglandin E2 signaling as measured by cAMP generation. These data indicate that loss of PGDH expression contributes to a more malignant bladder cancer phenotype and may be necessary for bladder cancer development and/or progression. (Am J

15-Hydroxyprostaglandin Dehydrogenase-derived 15-Keto-prostaglandin E2 Inhibits Cholangiocarcinoma Cell Growth through Interaction with Peroxisome Proliferator-activated Receptor-γ, SMAD2/3, and TAP63 Proteins

“…The NAD ϩ -dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes the oxidation of the 15(S)-hydroxyl group of PGE 2 , converting PGE 2 into 15-keto-PGE 2 (6). Consistent with the documented catabolism of PGE 2 by 15-PGDH, accumulating evidence suggests an important role of 15-PGDH in cancer development and progression (7)(8)(9)(10)(11)(12)(13)(14)(15). For example, 15-PGDH is down-regulated in several malignancies, such as colorectal, lung, gastric, bladder, and pancreatic cancers (7, 8, 10, 16 -20).…”

COX2/mPGES1/PGE 2 pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells

“…By inactivating endogenous PGE 2 , this enzyme provides a natural way of reducing the level of this lipid mediator. According to previous publications, expression of PGE 2 -forming enzyme COX2 in bladder cancer is frequently up-regulated (21), whereas expression of PGE 2 -degrading enzyme 15-PGDH is reduced (22). Moreover, earlier we demonstrated that the tumorinfiltrating myeloid cells also characterized by low 15-PGDH expression (23).…”

“…To obtain single-cell tumor suspensions, collected tumor tissues were disaggregated with collagenase mixture as described before (22). For isolation of PD-L1 + cells, we lysed red blood cells with ACK buffer and labeled cells with biotin-conjugated anti-PD-L1 Ab (Biolegend).…”

Oncolytic Herpes Simplex Virus 1 Encoding 15-Prostaglandin Dehydrogenase Mitigates Immune Suppression and Reduces Ectopic Primary and Metastatic Breast Cancer in Mice

“…PGE2 is negatively regulated by rapid conversion to 15-keto metabolites by 15-prostaglandin dehydrogenase (PGDH), an enzyme with both intra-and extracellular functions. Not surprisingly, 15-PGDH is a tumor suppressor (2,9,42,74), and loss of 15-PGDH expression in a variety of cancers often accompanies COX-2 upregulation and can be correlated with disease progression (2,35,66,67,70). Elevated levels of tumor-associated COX-2, coupled with a loss of PGDH expression, allows many tumors to maintain high levels of PGE2, which is a poor prognostic indicator and is considered to be an important step in the evolution of malignant cancers (reviewed in reference 21).…”