CF3DODA-Me induces apoptosis, degrades Sp1, and blocks the transformation phase of the blebbishield emergency program

Rikiya Taoka; Goodwin G Jinesh; Wenrui Xue; Stephen Safe; Ashish M Kamat

doi:10.1007/s10495-017-1359-1

CF₃DODA-Me induces apoptosis, degrades Sp1, and blocks the transformation phase of the blebbishield emergency program

Apoptosis. 2017 May;22(5):719-729. doi: 10.1007/s10495-017-1359-1.

Authors

Rikiya Taoka¹, Goodwin G Jinesh², Wenrui Xue¹, Stephen Safe³, Ashish M Kamat⁴

Affiliations

¹ Department of Urology, Unit 1373, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
² Department of Urology, Unit 1373, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA. goodwinjinesh@gmail.com.
³ Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, USA.
⁴ Department of Urology, Unit 1373, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA. akamat@mdanderson.org.

PMID: 28283889
DOI: 10.1007/s10495-017-1359-1

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.

Keywords: Blebbishields; Cellular transformation; K-Ras; Sp1; VEGFR2.

MeSH terms

Apoptosis / drug effects
Apoptosis / genetics*
Caspase 3 / genetics
Cell Line, Tumor
Cell Transformation, Neoplastic / drug effects
Cell Transformation, Neoplastic / genetics
Gene Expression Regulation, Neoplastic / drug effects
Glycyrrhetinic Acid / administration & dosage
Glycyrrhetinic Acid / analogs & derivatives
Humans
Hydrocarbons, Fluorinated / administration & dosage*
Hydrocarbons, Fluorinated / chemistry
Neoplastic Stem Cells / metabolism
Neoplastic Stem Cells / pathology
Reactive Oxygen Species / metabolism
Ribosomal Protein S6 Kinases, 70-kDa / genetics
Sp1 Transcription Factor / genetics*
Triterpenes / administration & dosage
Vascular Endothelial Growth Factor A / genetics*
Vascular Endothelial Growth Factor Receptor-2 / genetics*

Substances

Hydrocarbons, Fluorinated
Reactive Oxygen Species
Sp1 Transcription Factor
SP1 protein, human
Triterpenes
VEGFA protein, human
Vascular Endothelial Growth Factor A
KDR protein, human
Vascular Endothelial Growth Factor Receptor-2
Ribosomal Protein S6 Kinases, 70-kDa
CASP3 protein, human
Caspase 3
Glycyrrhetinic Acid