Inhibition of adult T-cell leukemia cell proliferation by polymerized proanthocyanidin from blueberry leaves through JAK proteolysis

Cancer Sci. 2022 Apr;113(4):1406-1416. doi: 10.1111/cas.15277. Epub 2022 Feb 13.


We have previously reported that the proanthocyanidin (PAC) fraction of blueberry leaf extract (BB-PAC) inhibits the proliferation of HTLV-1-infected adult T-cell leukemia (ATL) by inducing apoptosis. In the present study, we further analyzed the structure of BB-PAC and elucidated the molecular mechanism underlying the inhibitory function of HTLV-1-infected and ATL cells. After hot water extraction with fractionation with methanol-acetone, BB-PAC was found to be concentrated in fractions 4 to 7 (Fr7). The strongest inhibition of ATL cell growth was observed with Fr7, which contained the highest BB-PAC polymerization degree of 14. The basic structure of BB-PAC is mainly B-type bonds, with A-type bonds (7.1%) and cinchonain I units as the terminal unit (6.1%). The molecular mechanism of cytotoxicity observed around Fr7 against ATL cells was the degradation of JAK1 to 3 and the dephosphorylation of STAT3/5, which occurs by proteasome-dependent proteolysis, confirming that PAC directly binds to heat shock protein 90 (HSP90). JAK degradation was caused by proteasome-dependent proteolysis, and we identified the direct binding of PAC to HSP90. In addition, the binding of cochaperone ATPase homolog 1 (AHA1) to HSP90, which is required for activation of the cofactor HSP90, was inhibited by BB-PAC treatment. Therefore, BB-PAC inhibited the formation of the HSP90/AHA1 complex and promoted the degradation of JAK protein due to HSP90 dysfunction. These results suggest that the highly polymerized PAC component from blueberry leaves has great potential as a preventive and therapeutic agent against HTLV-1-infected and ATL cells.

Keywords: ATL; HSP90; JAK/STAT; blueberry leaf; proanthocyanidin.

MeSH terms

  • Adult
  • Blueberry Plants* / chemistry
  • Blueberry Plants* / metabolism
  • Cell Proliferation
  • HSP90 Heat-Shock Proteins / metabolism
  • Human T-lymphotropic virus 1*
  • Humans
  • Leukemia-Lymphoma, Adult T-Cell* / drug therapy
  • Leukemia-Lymphoma, Adult T-Cell* / metabolism
  • Polymerization
  • Proanthocyanidins
  • Proteasome Endopeptidase Complex / metabolism
  • Proteolysis


  • HSP90 Heat-Shock Proteins
  • Proanthocyanidins
  • proanthocyanidin
  • Proteasome Endopeptidase Complex