HIF-1α suppressing small molecule, LW6, inhibits cancer cell growth by binding to calcineurin b homologous protein 1

Beom Seok Kim, Kyeong Lee, Hye Jin Jung, Deepak Bhattarai, Ho Jeong Kwon

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Hypoxia inducible factor-1 alpha (HIF-1α) plays an important role in angiogenesis and metastasis and is a promising therapeutic target for the development of anti-cancer drugs. We recently developed a new synthetic small molecule inhibitor of HIF-1α, LW6, which results in inhibition of angiogenesis. To investigate its underlying mechanism, target protein identification was conducted by reverse chemical proteomics using phage display. We identified calcineurin b homologous protein 1 (CHP1) as a target protein of LW6, which specifically binds to CHP1 in a Ca 2+ dependent manner. Covalent labeling of LW6 using photoaffinity and click chemistry demonstrated its co-localization with CHP1 in live cells. HIF-1α was decreased by CHP1 knockdown in HepG2 cells, and angiogenesis was not induced in HUVEC cells by treatment with conditioned media from CHP1 knockdown cells compared to the control. These data demonstrated that LW6 inhibited HIF-1α stability via direct binding with CHP1 resulting in suppression of angiogenesis, providing a new insight into the role of CHP1 in HIF-1α regulation. LW6 could serve as a new chemical probe to explore CHP1 function.

Original languageEnglish
Pages (from-to)14-20
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume458
Issue number1
DOIs
Publication statusPublished - 2015 Feb 27

Fingerprint

Hypoxia-Inducible Factor 1
Calcineurin
Cell growth
Molecules
Growth
Neoplasms
Proteins
Click Chemistry
Bacteriophages
Human Umbilical Vein Endothelial Cells
Hep G2 Cells
Conditioned Culture Medium
Proteomics
Labeling
Display devices
Neoplasm Metastasis

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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title = "HIF-1α suppressing small molecule, LW6, inhibits cancer cell growth by binding to calcineurin b homologous protein 1",
abstract = "Hypoxia inducible factor-1 alpha (HIF-1α) plays an important role in angiogenesis and metastasis and is a promising therapeutic target for the development of anti-cancer drugs. We recently developed a new synthetic small molecule inhibitor of HIF-1α, LW6, which results in inhibition of angiogenesis. To investigate its underlying mechanism, target protein identification was conducted by reverse chemical proteomics using phage display. We identified calcineurin b homologous protein 1 (CHP1) as a target protein of LW6, which specifically binds to CHP1 in a Ca 2+ dependent manner. Covalent labeling of LW6 using photoaffinity and click chemistry demonstrated its co-localization with CHP1 in live cells. HIF-1α was decreased by CHP1 knockdown in HepG2 cells, and angiogenesis was not induced in HUVEC cells by treatment with conditioned media from CHP1 knockdown cells compared to the control. These data demonstrated that LW6 inhibited HIF-1α stability via direct binding with CHP1 resulting in suppression of angiogenesis, providing a new insight into the role of CHP1 in HIF-1α regulation. LW6 could serve as a new chemical probe to explore CHP1 function.",
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HIF-1α suppressing small molecule, LW6, inhibits cancer cell growth by binding to calcineurin b homologous protein 1. / Kim, Beom Seok; Lee, Kyeong; Jung, Hye Jin; Bhattarai, Deepak; Kwon, Ho Jeong.

In: Biochemical and Biophysical Research Communications, Vol. 458, No. 1, 27.02.2015, p. 14-20.

Research output: Contribution to journalArticle

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