Problematic 15‐PGDH: The Link between 15‐PGDH and Uncontrolled Tissue Growth

Abstract

15‐Hydroxyprostaglandin dehydrogenase (15‐PGDH) is the key enzyme that catalyzes the degradation of prostaglandin E2 (PGE2). The expression of 15‐PGDH is ubiquitously down‐regulated in various cancers. Whereas, overexpression of 15‐PGDH in cancer cells causes apoptosis, cell cycle arrest, and inhibition of metastasis, and hence considered as a tumor suppressor. Hypermethylation of CpG islands in the gene promoter region is an important mechanism to silence the expression of 15‐PGDH and contributes to cancer formation. 15‐PGDH physiologically antagonizes cyclooxygenase‐2 (COX‐2), an enzyme involved in inflammation and carcinogenesis. Therefore, downregulation of 15‐PGDH and overexpression of COX‐2 may coordinately increase the levels of PGE2 and exacerbate the carcinogenic process. 15‐Deoxy‐Δ 12,14 ‐prostaglandin J2, a product of the COX‐2 enzymatic pathway, upregulates the expression of 15‐PGDH in breast cancer MDA‐MD‐231 cells in a negative feedback loop. 15‐PGDH is directly regulated by the TGF‐tumor suppressor pathway. In addition to cancer research, current research involves investigating 15‐PGDH as a potential avenue for tissue regeneration. Inhibition of 15‐PGDH has been found to potentiate hematopoietic recovery in mice receiving a bone marrow. 15‐PGDH has also been found to play a central role in determination of active prostaglandin concentrations during pregnancy and may be competitively regulated by progesterone and cortisol. Mutations in the gene coding for 15‐PGDH can also cause digital clubbing, the swelling of the distal parts of the finger. Research on 15‐PGDH will unlock treatment methods for patients suffering from a wide variety of illnesses. We printed a 3D model of the 15‐PGDH protein structure to investigate the relationship between structure and function.Support or Funding InformationWalton High School SMART (Students Modeling a Research Topic) Team is sponsored by Milwaukee School of Engineering.