title: Mammalian target of rapamycin complex 1 and cyclooxygenase 2 pathways cooperatively exacerbate endometrial cancer.
abstract: The underlying causes of endometrial cancer (EMC) are poorly understood, and treatment options for patients with advanced stages of the disease are limited. Mutations in the phosphatase and tensin homologue gene are frequently detected in EMC. Cyclooxygenase 2 (Cox2) and mammalian target of rapamycin complex 1 (mTORC1) are known downstream targets of the phosphatase and tensin homologue protein, and their activities are up-regulated in EMC. However, it is not clear whether Cox2 and mTORC1 are crucial players in cancer progression or whether they work in parallel or cooperatively. In this study, we used a Cox2 inhibitor, celecoxib, and an mTORC1 inhibitor, rapamycin, in mouse models of EMC and in human EMC cell lines to explore the interactive roles of Cox2 and mTORC1 signaling. We found that a combined treatment with celecoxib and rapamycin markedly reduces EMC progression. We also observed that rapamycin reduces Cox2 expression, whereas celecoxib reduces mTORC1 activity. These results suggest that Cox2 and mTORC1 signaling is cross-regulated and cooperatively exacerbate EMC.
authors: Division of Reproductive Sciences, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address: takiko.daikoku@cchmc.org.
authors: Takiko
authors: T
authors: Daikoku
authors: Division of Reproductive Sciences, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Jumpei
authors: J
authors: Terakawa
authors: Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Md M
authors: MM
authors: Hossain
authors: Division of Reproductive Sciences, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Mikihiro
authors: M
authors: Yoshie
authors: Division of Molecular Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Monica
authors: M
authors: Cappelletti
authors: Department of Cancer Biology, University of Texas MD Anderson Medical Cancer Center, Houston, Texas.
authors: Peiying
authors: P
authors: Yang
authors: Department of Pathology and Laboratory Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York.
authors: Lora H
authors: LH
authors: Ellenson
authors: Division of Reproductive Sciences, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address: sk.dey@cchmc.org.
authors: Sudhansu K
authors: SK
authors: Dey
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D000068579:Celecoxib; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D016889:Endometrial Neoplasms / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; D052246:Cyclooxygenase 2 Inhibitors; D046912:Multiprotein Complexes; D011720:Pyrazoles; D013449:Sulfonamides; D051546:Cyclooxygenase 2; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D000068579:Celecoxib; D020123:Sirolimus