Targeting prion-like protein doppel selectively suppresses tumor angiogenesis

Taslim A. Al-Hilal, Seung Woo Chung, Jeong Uk Choi, Farzana Alam, Jooho Park, Seong Who Kim, Sang Yoon Kim, Fakhrul Ahsan, In-San Kim, Youngro Byun

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Controlled and site-specific regulation of growth factor signaling remains a major challenge for current antiangiogenic therapies, as these antiangiogenic agents target normal vasculature as well tumor vasculature. In this article, we identified the prion-like protein doppel as a potential therapeutic target for tumor angiogenesis. We investigated the interactions between doppel and VEGFR2 and evaluated whether blocking the doppel/VEGFR2 axis suppresses the process of angiogenesis. We discovered that tumor endothelial cells (TECs), but not normal ECs, express doppel; tumors from patients and mouse xenografts expressed doppel in their vasculatures. Induced doppel overexpression in ECs enhanced vascularization, whereas doppel constitutively colocalized and complexed with VEGFR2 in TECs. Doppel inhibition depleted VEGFR2 from the cell membrane, subsequently inducing the internalization and degradation of VEGFR2 and thereby attenuating VEGFR2 signaling. We also synthesized an orally active glycosaminoglycan (LHbisD4) that specifically binds with doppel. We determined that LHbisD4 concentrates over the tumor site and that genetic loss of doppel in TECs decreases LHbisD4 binding and targeting both in vitro and in vivo. Moreover, LHbisD4 eliminated VEGFR2 from the cell membrane, prevented VEGF binding in TECs, and suppressed tumor growth. Together, our results demonstrate that blocking doppel can control VEGF signaling in TECs and selectively inhibit tumor angiogenesis.

Original languageEnglish
Pages (from-to)1251-1266
Number of pages16
JournalJournal of Clinical Investigation
Volume126
Issue number4
DOIs
Publication statusPublished - 2016 Apr 1

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Neoplasms
Endothelial Cells
Vascular Endothelial Growth Factor A
Prion Proteins
Cell Membrane
Angiogenesis Inhibitors
Glycosaminoglycans
Heterografts
Intercellular Signaling Peptides and Proteins
Therapeutics
Growth

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Al-Hilal, T. A., Chung, S. W., Choi, J. U., Alam, F., Park, J., Kim, S. W., ... Byun, Y. (2016). Targeting prion-like protein doppel selectively suppresses tumor angiogenesis. Journal of Clinical Investigation, 126(4), 1251-1266. https://doi.org/10.1172/JCI83427

Targeting prion-like protein doppel selectively suppresses tumor angiogenesis. / Al-Hilal, Taslim A.; Chung, Seung Woo; Choi, Jeong Uk; Alam, Farzana; Park, Jooho; Kim, Seong Who; Kim, Sang Yoon; Ahsan, Fakhrul; Kim, In-San; Byun, Youngro.

In: Journal of Clinical Investigation, Vol. 126, No. 4, 01.04.2016, p. 1251-1266.

Research output: Contribution to journalArticle

Al-Hilal, TA, Chung, SW, Choi, JU, Alam, F, Park, J, Kim, SW, Kim, SY, Ahsan, F, Kim, I-S & Byun, Y 2016, 'Targeting prion-like protein doppel selectively suppresses tumor angiogenesis', Journal of Clinical Investigation, vol. 126, no. 4, pp. 1251-1266. https://doi.org/10.1172/JCI83427
Al-Hilal TA, Chung SW, Choi JU, Alam F, Park J, Kim SW et al. Targeting prion-like protein doppel selectively suppresses tumor angiogenesis. Journal of Clinical Investigation. 2016 Apr 1;126(4):1251-1266. https://doi.org/10.1172/JCI83427
Al-Hilal, Taslim A. ; Chung, Seung Woo ; Choi, Jeong Uk ; Alam, Farzana ; Park, Jooho ; Kim, Seong Who ; Kim, Sang Yoon ; Ahsan, Fakhrul ; Kim, In-San ; Byun, Youngro. / Targeting prion-like protein doppel selectively suppresses tumor angiogenesis. In: Journal of Clinical Investigation. 2016 ; Vol. 126, No. 4. pp. 1251-1266.
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