title: Slug expression inhibits calcitriol-mediated sensitivity to radiation in colorectal cancer.
abstract: Recently, a reciprocal relationship between calcitriol and epithelial-to-mesenchymal transition has been described. Therefore, we hypothesized that calcitriol (1α,25-dihydroxyvitamin D₃) would enhance radiation sensitivity in colorectal cancer regulated by epithelial mesenchymal transition. Vitamin-D receptor, E-cadherin and vimentin protein as well as E-cadherin, Snail and Slug mRNA levels were assessed in a panel of human colorectal cancer cell lines at baseline and in response calcitriol. We defined cell lines as calcitriol sensitive based on demonstrating an enhanced epithelial phenotype with increased E-cadherin, reduced vimentin and decreased expression of Snail and Slug as well as decreased cellular migration in response to calcitriol. In calcitriol sensitive cells, including DLD-1 and HCT116, 24 h calcitriol pre-treatment enhanced the radiation sensitivity by 2.3- and 2.6-fold, respectively, at 4 Gy (P < 0.05). In contrast, SW620 cells with high baseline mesenchymal features including high Slug and vimentin expression with low E-cadherin expression demonstrated no significant radiation sensitizing response to calcitriol treatment. Similarly, transfection of Slug in the calcitriol sensitive colon cancer cell lines, DLD-1 and HCT 116, completely inhibited the radiation sensitizing effect of calcitriol. Collectively, we demonstrate that calcitriol can enhance the therapeutic effects of radiation in colon cancer cells and Slug expression mitigates this observed effect potentially representing an effective biomarker for calcitriol therapy.
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Findlay
authors.forename: R Eric
authors.initials: RE
authors.lastname: Moretz
authors.forename: Cindy
authors.initials: C
authors.lastname: Wang
authors.forename: Silvia G
authors.initials: SG
authors.lastname: Vaena
authors.forename: Savannah G
authors.initials: SG
authors.lastname: Bandurraga
authors.forename: Michael
authors.initials: M
authors.lastname: Ashenafi
authors.forename: David T
authors.initials: DT
authors.lastname: Marshall
authors.forename: Dennis K
authors.initials: DK
authors.lastname: Watson
authors.forename: E Ramsay
authors.initials: ER
authors.lastname: Camp
mesh_terms: D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002117:Calcitriol / Q000494:pharmacology*; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects / Q000528:radiation effects; D002465:Cell Movement / Q000187:drug effects / Q000528:radiation effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000528:radiation effects; D005455:Fluorescent Antibody Technique; D005720:Gamma Rays; D006801:Humans; D012333:RNA, Messenger / Q000235:genetics; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014746:Vimentin / Q000235:genetics / Q000378:metabolism
chemical_list: D015820:Cadherins; D002120:Calcium Channel Agonists; D012333:RNA, Messenger; D011838:Radiation-Sensitizing Agents; D018167:Receptors, Calcitriol; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D014746:Vimentin; D002117:Calcitriol
keywords: EMT; Slug; cancer; colorectal; radiation; vitamin D