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Apoptosis

, Volume 22, Issue 5, pp 719–729 | Cite as

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

  • Rikiya Taoka
  • Goodwin G. JineshEmail author
  • Wenrui Xue
  • Stephen Safe
  • Ashish M. KamatEmail author
Article

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 VEGFR2 K-Ras Sp1 

Abbreviations

Sp1

Specificity1

VEGFR2

Vascular endothelial growth factor receptor 2

VEGF

Vascular endothelial growth factor

PKC-ζ

Protein kinase-C-ζ

CHX

Cycloheximide

ROS

Reactive oxygen species

GST

Glutathione-S-transferase

Notes

Acknowledgements

The authors sincerely thank Dr. David J. McConkey (The University of Texas MD Anderson Cancer Center) for various reagents; Dr. Channing Der (University of North Carolina) and Dr. Santosh Chauhan (University of New Mexico) for plasmids (see GST pulldown section for details); Ms. Stephanie Deming for editorial help with the manuscript; and Ms. I-Ling Lee for technical help.

Author contributions

R.T. performed all experiments except those in Fig. 5, interpreted the data, and wrote the manuscript. G.J.G. conceived the hypothesis, designed the study, performed the experiments in Fig. 5 and prepared Fig. 6, interpreted the data, and wrote the manuscript. W.X. did part of the dose finding study. S.S. provided CF3DODA-Me. A.M.K. interpreted the data and provided scientific and editorial oversight.

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.

Ethical approval

All experiments comply with the current laws of United States of America.

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Copyright information

© Springer Science+Business Media New York (outside the USA) 2017

Authors and Affiliations

  1. 1.Department of Urology, Unit 1373The University of Texas MD Anderson Cancer CenterHoustonUSA
  2. 2.Department of Veterinary Physiology and PharmacologyTexas A&M UniversityCollege StationUSA

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