title: Targeting the Nuclear Cathepsin L CCAAT Displacement Protein/Cut Homeobox Transcription Factor-Epithelial Mesenchymal Transition Pathway in Prostate and Breast Cancer Cells with the Z-FY-CHO Inhibitor.
abstract: The epithelial mesenchymal transition (EMT) promotes tumor migration and invasion by downregulating epithelial markers such as E-cadherin and upregulating mesenchymal markers such as vimentin. Cathepsin L (Cat L) is a cysteine protease that can proteolytically activate CCAAT displacement protein/cut homeobox transcription factor (CUX1). We hypothesized that nuclear Cat L may promote EMT via CUX1 and that this could be antagonized with the Cat L-specific inhibitor Z-FY-CHO. Mesenchymal prostate (ARCaP-M and ARCaP-E overexpressing Snail) and breast (MDA-MB-468, MDA-MB-231, and MCF-7 overexpressing Snail) cancer cells expressed lower E-cadherin activity, higher Snail, vimentin, and Cat L activity, and a p110/p90 active CUX1 form, compared to epithelial prostate (ARCaP-E and ARCaP-Neo) and breast (MCF-7 and MCF-7 Neo) cancer cells. There was increased binding of CUX1 to Snail and the E-cadherin promoter in mesenchymal cells compared to epithelial prostate and breast cells. Treatment of mesenchymal cells with the Cat L inhibitor Z-FY-CHO led to nuclear-to-cytoplasmic relocalization of Cat L, decreased binding of CUX1 to Snail and the E-cadherin promoter, reversed EMT, and decreased cell migration/invasion. Overall, our novel data suggest that a positive feedback loop between Snail-nuclear Cat L-CUX1 drives EMT, which can be antagonized by Z-FY-CHO. Therefore, Z-FY-CHO may be an important therapeutic tool to antagonize EMT and cancer progression.
authors.affiliation: Center for Cancer Research and Therapeutic Development, Department of Biological Sciences, Clark Atlanta University, Atlanta, Georgia, USA.
authors.forename: Liza J
authors.initials: LJ
authors.lastname: Burton
authors.affiliation: Center for Cancer Research and Therapeutic Development, Department of Biological Sciences, Clark Atlanta University, Atlanta, Georgia, USA.
authors.forename: Jodi
authors.initials: J
authors.lastname: Dougan
authors.affiliation: Center for Cancer Research and Therapeutic Development, Department of Biological Sciences, Clark Atlanta University, Atlanta, Georgia, USA.
authors.forename: Jasmine
authors.initials: J
authors.lastname: Jones
authors.affiliation: Center for Cancer Research and Therapeutic Development, Department of Biological Sciences, Clark Atlanta University, Atlanta, Georgia, USA.
authors.forename: Bethany N
authors.initials: BN
authors.lastname: Smith
authors.affiliation: Center for Cancer Research and Therapeutic Development, Department of Biological Sciences, Clark Atlanta University, Atlanta, Georgia, USA.
authors.forename: Diandra
authors.initials: D
authors.lastname: Randle
authors.affiliation: Center for Cancer Research and Therapeutic Development, Department of Biological Sciences, Clark Atlanta University, Atlanta, Georgia, USA.
authors.forename: Veronica
authors.initials: V
authors.lastname: Henderson
authors.affiliation: Center for Cancer Research and Therapeutic Development, Department of Biological Sciences, Clark Atlanta University, Atlanta, Georgia, USA vodero_marah@cau.edu.
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Odero-Marah
mesh_terms: D015703:Antigens, CD; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D056668:Cathepsin L / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology*; D004151:Dipeptides / Q000494:pharmacology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D025461:Feedback, Physiological / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D008648:Mesoderm / Q000187:drug effects / Q000473:pathology; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D000071250:Snail Family Transcription Factors / Q000378:metabolism; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; C080632:CUX1 protein, human; D015820:Cadherins; D004151:Dipeptides; D018398:Homeodomain Proteins; C101290:N-(benzyloxycarbonyl)-phenylalanyl-tyrosinal; D009687:Nuclear Proteins; D011480:Protease Inhibitors; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D056668:Cathepsin L
keywords: CDP/Cux; EMT; Snail; Z-FY-CHO; cathepsin L