Journal
CANCER SCIENCE
Volume 113, Issue 4, Pages 1406-1416Publisher
WILEY
DOI: 10.1111/cas.15277
Keywords
ATL; blueberry leaf; HSP90; JAK; STAT; proanthocyanidin
Categories
Funding
- Japan Society for the Promotion of Science [17H03581, 18K07238, 21K07128]
- Shinnihon Foundation of Advanced Medical Treatment Research
- Takeda Science Foundation
- Grants-in-Aid for Scientific Research [17H03581, 18K07238, 21K07128] Funding Source: KAKEN
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The highly polymerized proanthocyanidin component from blueberry leaves has been shown to inhibit the proliferation of HTLV-1-infected and ATL cells by binding to heat shock protein 90 (HSP90) and promoting the degradation of JAK protein through proteasome-dependent proteolysis. The findings suggest that it has great potential as a preventive and therapeutic agent.
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.
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