Inhibition of adult T-cell leukemia cell proliferation by polymerized proanthocyanidin from blueberry leaves through JAK proteolysis.
Inhibition of adult T-cell leukemia cell proliferation by polymerized proanthocyanidin from blueberry leaves through JAK proteolysis.
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DOI：
10.1111/cas.15277
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发表时间：
2022-04
期刊：
影响因子：
5.7
通讯作者：
Morishita K
中科院分区：
文献类型：
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作者：
Ichikawa T;Sugamoto K;Matsuura Y;Kunitake H;Shimoda K;Morishita K
我们之前报道过蓝莓叶提取物 (BB-PAC) 中的原花青素 (PAC) 部分通过诱导细胞凋亡来抑制 HTLV-1 感染的成人 T 细胞白血病 (ATL) 的增殖。在本研究中，我们进一步分析了 BB-PAC 的结构，并阐明了 HTLV-1 感染和 ATL 细胞抑制功能的分子机制。热水萃取并用甲醇-丙酮分馏后，发现 BB-PAC 浓缩在级分 4 至 7 (Fr7) 中。 Fr7对ATL细胞生长的抑制作用最强，其BB-PAC聚合度最高为14。BB-PAC的基本结构主要是B型键，A型键（7.1%）和金鸡纳素I单元为末端单元（6.1%）。在 Fr7 周围观察到的针对 ATL 细胞的细胞毒性的分子机制是 JAK1 降解为 3 和 STAT3/5 去磷酸化，这是通过蛋白酶体依赖性蛋白水解发生的，证实 PAC 直接与热休克蛋白 90 (HSP90) 结合。 JAK 降解是由蛋白酶体依赖性蛋白水解引起的，我们确定了 PAC 与 HSP90 的直接结合。此外，辅伴侣 ATP 酶同源物 1 (AHA1) 与 HSP90 的结合（这是激活辅因子 HSP90 所必需的）被 BB-PAC 处理抑制。因此，BB-PAC抑制HSP90/AHA1复合物的形成，并促进由于HSP90功能障碍而导致的JAK蛋白的降解。这些结果表明，来自蓝莓叶的高度聚合的 PAC 成分作为针对 HTLV-1 感染和 ATL 细胞的预防和治疗剂具有巨大的潜力。蓝莓叶中的原花青素通过抑制热休克蛋白90来降解成人T细胞白血病细胞中的JAK蛋白，并抑制JAK/STAT信号传导，导致细胞死亡。
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. Proanthocyanidins in blueberry leaves degrade JAK protein in adult T‐cell leukemia cells by inhibiting heat shock protein 90, and inhibit JAK/STAT signaling, causing cell death.
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DOI：
10.1158/1078-0432.ccr-11-1541
发表时间：
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期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
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3.7
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影响因子：
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作者：
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通讯作者：
Levine, Ross L.
影响因子：
5.7
作者：
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DOI：
10.1080/01635581.2013.783602
发表时间：
2014
期刊：
Nutrition and cancer
影响因子：
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作者：
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Agarwal C