title: Modulation of NKG2D ligand expression and metastasis in tumors by spironolactone via RXRγ activation.
abstract: Tumor metastasis and lack of NKG2D ligand (NKG2DL) expression are associated with poor prognosis in patients with colon cancer. Here, we found that spironolactone (SPIR), an FDA-approved diuretic drug with a long-term safety profile, can up-regulate NKG2DL expression in multiple colon cancer cell lines by activating the ATM-Chk2-mediated checkpoint pathway, which in turn enhances tumor elimination by natural killer cells. SPIR can also up-regulate the expression of metastasis-suppressor genes TIMP2 and TIMP3, thereby reducing tumor cell invasiveness. Although SPIR is an aldosterone antagonist, its antitumor effects are independent of the mineralocorticoid receptor pathway. By screening the human nuclear hormone receptor siRNA library, we identified retinoid X receptor γ (RXRγ) instead as being indispensable for the antitumor functions of SPIR. Collectively, our results strongly support the use of SPIR or other RXRγ agonists with minimal side effects for colon cancer prevention and therapy.
authors.affiliation: Department of Bone Marrow Transplantation and Cellular Therapy; 2 Department of Chemical Biology & Therapeutics; and 3 Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
authors.forename: Wai-Hang
authors.initials: WH
authors.lastname: Leung
authors.forename: Queenie P
authors.initials: QP
authors.lastname: Vong
authors.forename: Wenwei
authors.initials: W
authors.lastname: Lin
authors.forename: Laura
authors.initials: L
authors.lastname: Janke
authors.forename: Taosheng
authors.initials: T
authors.lastname: Chen
authors.forename: Wing
authors.initials: W
authors.lastname: Leung
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000556:secondary; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D047491:Retinoid X Receptor gamma / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics; D015398:Signal Transduction; D013148:Spironolactone / Q000494:pharmacology*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C527085:KLRK1 protein, human; D008024:Ligands; C099187:MHC class I-related chain A; C098080:MICB antigen; D055655:NK Cell Lectin-Like Receptor Subfamily K; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D018161:Receptors, Mineralocorticoid; D047491:Retinoid X Receptor gamma; C560823:TIMP2 protein, human; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; C423231:ULBP1 protein, human; C423230:ULBP2 protein, human; C423229:ULBP3 protein, human; D019716:Tissue Inhibitor of Metalloproteinase-2; D013148:Spironolactone