title: Progesterone and 1,25-dihydroxyvitamin D₃ inhibit endometrial cancer cell growth by upregulating semaphorin 3B and semaphorin 3F.
abstract: Class 3 semaphorins (SEMA), SEMA3B and SEMA3F, are secreted proteins that regulate angiogenesis, tumor growth, and metastasis by binding to their transmembrane receptor complex consisting of plexins and neuropilins (NP). Expression of SEMAs and their receptors was assessed in tissue microarrays by immunohistochemistry. SEMA3B, SEMA3F, and plexin A3 were expressed strongly in normal endometrial tissues, whereas grade-dependent decreases were found in endometrial carcinomas. No change was observed in the expression of plexin A1, NP1, and NP2 in normal versus endometrial cancer tissues. Endometrial cancer cells showed decreased expression of SEMA3B, SEMA3F, and plexin A3 compared with their normal counterparts. Treatment of cancer cells with progesterone (P4) and 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] for a period of 72 hours induced a significant upregulation of SEMA3B and SEMA3F as well as inhibited growth of cancer cells by increasing caspase-3 activity. Cotreatment of cell lines with P4 or 1,25(OH)(2)D(3) and their respective antagonists confirmed the specificity of their actions. Transfection of siRNA-targeting SEMA3B and SEMA3F in endometrial cancer cells attenuated P4 or 1,25(OH)(2)D(3)-induced growth inhibition. Restoration of SEMA3B or SEMA3F expression in cancer cells caused growth inhibition, reduced soft agar colony formation, and cell invasiveness by inhibiting expression of matrix metalloproteinase-2 (MMP-2), MMP-9, integrin αvβ3, and proangiogenic genes and by upregulating antiangiogenic genes. Thus, we have identified two new P4 and 1,25(OH)(2)D(3)-regulated antitumor genes for endometrial cancer. These results suggest that the loss of SEMAs contribute to the malignant phenotype of endometrial cancer cells and that reexpression of SEMAs by ectopic expression or with anticancer agents P4 or 1,25(OH)(2)D(3) can be a promising therapeutic treatment against endometrial cancer.
authors.affiliation: Uniformed Services University of the Health Sciences, Department of Obstetrics and Gynecology, Bethesda, MD 20814, USA.
authors.forename: Huyen
authors.initials: H
authors.lastname: Nguyen
authors.forename: Vessela S
authors.initials: VS
authors.lastname: Ivanova
authors.forename: Leyla
authors.initials: L
authors.lastname: Kavandi
authors.forename: Gustavo C
authors.initials: GC
authors.lastname: Rodriguez
authors.forename: George L
authors.initials: GL
authors.lastname: Maxwell
authors.forename: Viqar
authors.initials: V
authors.lastname: Syed
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D011374:Progesterone / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D039961:Semaphorins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C097871:PLXNA3 protein, human; D011956:Receptors, Cell Surface; C409766:SEMA3B protein, human; C491230:SEMA3F protein, human; D039961:Semaphorins; D014807:Vitamin D; D011374:Progesterone; C097949:1,25-dihydroxyvitamin D