title: CF3DODA-Me induces apoptosis, degrades Sp1, and blocks the transformation phase of the blebbishield emergency program.
abstract: Cancer stem cells are capable of undergoing cellular transformation after commencement of apoptosis through the blebbishield emergency program in a VEGF-VEGFR2-dependent manner. Development of therapeutics targeting the blebbishield emergency program would thus be important in cancer therapy. Specificity protein 1 (Sp1) orchestrates the transcription of both VEGF and VEGFR2; hence, Sp1 could act as a therapeutic target. Here, we demonstrate that CF3DODA-Me induced apoptosis, degraded Sp1, inhibited the expression of multiple drivers of the blebbishield emergency program such as VEGFR2, p70S6K, and N-Myc through activation of caspase-3, inhibited reactive oxygen species; and inhibited K-Ras activation to abolish transformation from blebbishields as well as transformation in soft agar. These findings confirm CF3DODA-Me as a potential therapeutic candidate that can induce apoptosis and block transformation from blebbishields.
authors.affiliation: Department of Urology, Unit 1373, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
authors.forename: Rikiya
authors.initials: R
authors.lastname: Taoka
authors.affiliation: Department of Urology, Unit 1373, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA. goodwinjinesh@gmail.com.
authors.forename: Goodwin G
authors.initials: GG
authors.lastname: Jinesh
authors.affiliation: Department of Urology, Unit 1373, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
authors.forename: Wenrui
authors.initials: W
authors.lastname: Xue
authors.affiliation: Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
authors.affiliation: Department of Urology, Unit 1373, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA. akamat@mdanderson.org.
authors.forename: Ashish M
authors.initials: AM
authors.lastname: Kamat
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D053148:Caspase 3 / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006034:Glycyrrhetinic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000008:administration & dosage* / Q000737:chemistry; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000235:genetics*; D014315:Triterpenes / Q000008:administration & dosage; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics*
chemical_list: D006845:Hydrocarbons, Fluorinated; D017382:Reactive Oxygen Species; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; D014315:Triterpenes; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C505407:CASP3 protein, human; D053148:Caspase 3; D006034:Glycyrrhetinic Acid
keywords: Blebbishields; Cellular transformation; K-Ras; Sp1; VEGFR2