Cell Stress and Chaperones

, Volume 23, Issue 5, pp 1055–1068 | Cite as

Caffeic acid phenethyl ester (CAPE) possesses pro-hypoxia and anti-stress activities: bioinformatics and experimental evidences

  • Priyanshu Bhargava
  • Anjani Kumari
  • Jayarani F. Putri
  • Yoshiyuki Ishida
  • Keiji Terao
  • Sunil C. Kaul
  • Durai Sundar
  • Renu Wadhwa
Original Paper


Honeybee propolis and its bioactive component, caffeic acid phenethyl ester (CAPE), are known for a variety of therapeutic potentials. By recruiting a cell-based reporter assay for screening of hypoxia-modulating natural drugs, we identified CAPE as a pro-hypoxia factor. In silico studies were used to probe the capacity of CAPE to interact with potential hypoxia-responsive proteins. CAPE could not dock into hypoxia inducing factor (HIF-1), the master regulator of hypoxia response pathway. On the other hand, it was predicted to bind to factor inhibiting HIF (FIH-1). The active site residue (Asp201) of FIH-1α was involved in hydrogen bond formation with CAPE and its analogue, caffeic acid methyl ester (CAME), especially in the presence of Fe and 2-oxoglutaric acid (OGA). We provide experimental evidence that the low doses of CAPE, that did not cause cytotoxicity or anti-migratory effect, activated HIF-1α and inhibited stress-induced protein aggregation, a common cause of age-related pathologies. Furthermore, by structural homology search, we explored and found candidate compounds that possess stronger FIH-1 binding capacity. These compounds could be promising candidates for modulating therapeutic potential of CAPE, and its recruitment in treatment of protein aggregation-based disorders.


Caffeic acid phenethyl ester Hypoxia inducible factor Factor inhibiting HIF-1α Pro-hypoxia Anti-stress molecules 



Computations were performed at the Bioinformatics Centre at IIT Delhi. DAILAB is supported by grants from the Department of Biotechnology (Government of India) and AIST (Japan).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

12192_2018_915_Fig8_ESM.png (362 kb)
Fig. S1

Molecular interaction of CAPE with C-terminal Activation Domain (CTAD) of HIF-1α: Binding of CAPE molecule (green) with CTAD of HIF-1α is shown. The amino acid residues involved in the interaction of the protein with the molecule are shown in pink. CAPE-CTAD did not show significant binding to HIF-1α. (PNG 362 kb)

12192_2018_915_MOESM1_ESM.tif (3.7 mb)
High Resolution Image (TIF 3777 kb)


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Copyright information

© Cell Stress Society International 2018

Authors and Affiliations

  1. 1.DAILAB, DBT-AIST International Center for Translational and Environmental Research (DAICENTER)National Institute of Advanced Industrial Science and Technology (AIST)TsukubaJapan
  2. 2.Graduate School of Life and Environmental SciencesUniversity of TsukubaTsukubaJapan
  3. 3.DAILAB, Department of Biochemical Engineering and BiotechnologyIndian Institute of Technology (IIT) DelhiNew DelhiIndia
  4. 4.CycloChem Co., LtdKobeJapan

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