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

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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.

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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

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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.

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    Authors and Affiliations

    1. Department of Urology, Unit 1373, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA

      Rikiya Taoka, Goodwin G. Jinesh, Wenrui Xue & Ashish M. Kamat

    2. Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, USA

      Stephen Safe

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    1. Rikiya Taoka
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    Correspondence to Goodwin G. Jinesh or Ashish M. Kamat.

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

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    Rikiya Taoka and Goodwin G. Jinesh have contributed equally to this work.

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    Taoka, R., Jinesh, G.G., Xue, W. et al. CF3DODA-Me induces apoptosis, degrades Sp1, and blocks the transformation phase of the blebbishield emergency program. Apoptosis 22, 719–729 (2017). https://doi.org/10.1007/s10495-017-1359-1

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