BIOMAT Database Logo BIOMAT Database Logo

Inhibition of adult T-cell leukemia cell proliferation by polymerized proanthocyanidin from blueberry leaves through JAK proteolysis. 2022

Tomonaga Ichikawa, and Kazuhiro Sugamoto, and Yasushi Matsuura, and Hisato Kunitake, and Kazuya Shimoda, and Kazuhiro Morishita
Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, University of Miyazaki, Miyazaki, Japan.

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.

UI MeSH Term Description Entries
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000328 Adult A person having attained full growth or maturity. Adults are of 19 through 44 years of age. For a person between 19 and 24 years of age, YOUNG ADULT is available. Adults
D015368 Human T-lymphotropic virus 1 A strain of PRIMATE T-LYMPHOTROPIC VIRUS 1 isolated from mature T4 cells in patients with T-lymphoproliferation malignancies. It causes adult T-cell leukemia (LEUKEMIA-LYMPHOMA, T-CELL, ACUTE, HTLV-I-ASSOCIATED), T-cell lymphoma (LYMPHOMA, T-CELL), and is involved in mycosis fungoides, SEZARY SYNDROME and tropical spastic paraparesis (PARAPARESIS, TROPICAL SPASTIC). ATLV,Adult T-Cell Leukemia-Lymphoma Virus I,HTLV-1,HTLV-I,Human T-Cell Leukemia Virus I,Leukemia Virus I, Human T-Cell,T-Cell Leukemia Virus I, Human,Adult T Cell Leukemia Lymphoma Virus I,Human T Cell Leukemia Virus I,Leukemia Lymphoma Virus I, Adult T Cell,Leukemia Virus I, Human T Cell,T Cell Leukemia Virus I, Human,Human T lymphotropic virus 1
D015459 Leukemia-Lymphoma, Adult T-Cell Aggressive T-Cell malignancy with adult onset, caused by HUMAN T-LYMPHOTROPIC VIRUS 1. It is endemic in Japan, the Caribbean basin, Southeastern United States, Hawaii, and parts of Central and South America and sub-Saharan Africa. ATLL,HTLV I Associated T Cell Leukemia Lymphoma,HTLV-Associated Leukemia-Lymphoma,HTLV-I-Associated T-Cell Leukemia-Lymphoma,Human T Lymphotropic Virus Associated Leukemia Lymphoma,Human T Lymphotropic Virus-Associated Leukemia-Lymphoma,Human T-Cell Leukemia-Lymphoma,Leukemia Lymphoma, Adult T Cell,Leukemia Lymphoma, T Cell, Acute, HTLV I Associated,Leukemia, Adult T-Cell,Leukemia-Lymphoma, T-Cell, Acute, HTLV-I-Associated,T Cell Leukemia Lymphoma, HTLV I Associated,T Cell Leukemia, Adult,T-Cell Leukemia, Adult,T-Cell Leukemia-Lymphoma, Adult,T-Cell Leukemia-Lymphoma, HTLV-I-Associated,Adult T-Cell Leukemia,Adult T-Cell Leukemia-Lymphoma,Adult T-Cell Leukemia-Lymphomas,Adult T-Cell Leukemias,HTLV Associated Leukemia Lymphoma,HTLV-Associated Leukemia-Lymphomas,HTLV-I-Associated T-Cell Leukemia-Lymphomas,Human T Cell Leukemia Lymphoma,Human T-Cell Leukemia-Lymphomas,Leukemia, Adult T Cell,Leukemia-Lymphoma, HTLV-Associated,Leukemia-Lymphoma, HTLV-I-Associated T-Cell,Leukemia-Lymphoma, Human T-Cell,Leukemia-Lymphomas, Adult T-Cell,Leukemia-Lymphomas, HTLV-Associated,Leukemia-Lymphomas, HTLV-I-Associated T-Cell,Leukemia-Lymphomas, Human T-Cell,Leukemias, Adult T-Cell,T Cell Leukemia Lymphoma, Adult,T-Cell Leukemia-Lymphoma, Human,T-Cell Leukemia-Lymphomas, Adult,T-Cell Leukemia-Lymphomas, HTLV-I-Associated,T-Cell Leukemia-Lymphomas, Human,T-Cell Leukemias, Adult
D044945 Proanthocyanidins Dimers and oligomers of flavan-3-ol units (CATECHIN analogs) linked mainly through C4 to C8 bonds to leucoanthocyanidins. They are structurally similar to ANTHOCYANINS but are the result of a different fork in biosynthetic pathways. Anthocyanidin Polymers,Tannin, Condensed,Condensed Tannin,Condensed Tannins,Procyanidins,Polymers, Anthocyanidin,Tannins, Condensed
D046988 Proteasome Endopeptidase Complex A large multisubunit complex that plays an important role in the degradation of most of the cytosolic and nuclear proteins in eukaryotic cells. It contains a 700-kDa catalytic sub-complex and two 700-kDa regulatory sub-complexes. The complex digests ubiquitinated proteins and protein activated via ornithine decarboxylase antizyme. 20S Proteasome,Ingensin,Macropain,Macroxyproteinase,Multicatalytic Endopeptidase Complex,Multicatalytic Proteinase,Prosome,Proteasome,Complex, Multicatalytic Endopeptidase,Complex, Proteasome Endopeptidase,Endopeptidase Complex, Multicatalytic,Endopeptidase Complex, Proteasome,Proteasome, 20S,Proteinase, Multicatalytic
D049109 Cell Proliferation All of the processes involved in increasing CELL NUMBER including CELL DIVISION. Cell Growth in Number,Cellular Proliferation,Cell Multiplication,Cell Number Growth,Growth, Cell Number,Multiplication, Cell,Number Growth, Cell,Proliferation, Cell,Proliferation, Cellular
D058105 Polymerization Chemical reaction in which monomeric components are combined to form POLYMERS (e.g., POLYMETHYLMETHACRYLATE). Polymerizations
D059748 Proteolysis Cleavage of proteins into smaller peptides or amino acids either by PROTEASES or non-enzymatically (e.g., Hydrolysis). It does not include Protein Processing, Post-Translational. Protein Degradation,Protein Digestion,Degradation, Protein,Degradations, Protein,Digestion, Protein,Digestions, Protein,Protein Degradations,Protein Digestions,Proteolyses
D018841 HSP90 Heat-Shock Proteins A class of MOLECULAR CHAPERONES whose members act in the mechanism of SIGNAL TRANSDUCTION by STEROID RECEPTORS. Heat-Shock Proteins 90,HSP90 Heat Shock Proteins,Heat Shock Proteins 90,Heat-Shock Proteins, HSP90

Related Publications

Tomonaga Ichikawa, and Kazuhiro Sugamoto, and Yasushi Matsuura, and Hisato Kunitake, and Kazuya Shimoda, and Kazuhiro Morishita
[Inhibition of proliferation of adult T-cell leukemia cells by celastrol].
September 2018, Sheng wu gong cheng xue bao = Chinese journal of biotechnology,
Tomonaga Ichikawa, and Kazuhiro Sugamoto, and Yasushi Matsuura, and Hisato Kunitake, and Kazuya Shimoda, and Kazuhiro Morishita
[Inhibition of proliferation by retinoic acid on adult T cell leukemia cells].
October 1996, Nihon Rinsho Men'eki Gakkai kaishi = Japanese journal of clinical immunology,
Tomonaga Ichikawa, and Kazuhiro Sugamoto, and Yasushi Matsuura, and Hisato Kunitake, and Kazuya Shimoda, and Kazuhiro Morishita
Proanthocyanidin from blueberry leaves suppresses expression of subgenomic hepatitis C virus RNA.
August 2009, The Journal of biological chemistry,
Tomonaga Ichikawa, and Kazuhiro Sugamoto, and Yasushi Matsuura, and Hisato Kunitake, and Kazuya Shimoda, and Kazuhiro Morishita
Proliferation of adult T cell leukemia/lymphoma cells is associated with the constitutive activation of JAK/STAT proteins.
December 1997, Proceedings of the National Academy of Sciences of the United States of America,
Tomonaga Ichikawa, and Kazuhiro Sugamoto, and Yasushi Matsuura, and Hisato Kunitake, and Kazuya Shimoda, and Kazuhiro Morishita
Inhibition of constitutively active Jak-Stat pathway suppresses cell growth of human T-cell leukemia virus type 1-infected T-cell lines and primary adult T-cell leukemia cells.
April 2006, Retrovirology,
Tomonaga Ichikawa, and Kazuhiro Sugamoto, and Yasushi Matsuura, and Hisato Kunitake, and Kazuya Shimoda, and Kazuhiro Morishita
mTOR inhibition and adult T-cell leukemia.
April 2009, Leukemia & lymphoma,
Tomonaga Ichikawa, and Kazuhiro Sugamoto, and Yasushi Matsuura, and Hisato Kunitake, and Kazuya Shimoda, and Kazuhiro Morishita
Prediction of the Adult T-Cell Leukemia Inhibitory Activity of Blueberry Leaves/Stems Using Direct-Injection Electron Ionization-Mass Spectrometry Metabolomics.
May 2022, Plants (Basel, Switzerland),
Tomonaga Ichikawa, and Kazuhiro Sugamoto, and Yasushi Matsuura, and Hisato Kunitake, and Kazuya Shimoda, and Kazuhiro Morishita
Inhibition of proliferation and CD25 down-regulation by retinoic acid in human adult T cell leukemia cells.
March 1997, Leukemia,
Tomonaga Ichikawa, and Kazuhiro Sugamoto, and Yasushi Matsuura, and Hisato Kunitake, and Kazuya Shimoda, and Kazuhiro Morishita
Retraction. Inhibition of constitutively active Jak-Stat pathway suppresses cell growth of human T-cell leukemia virus type 1-infected T-cell lines and primary adult T-cell leukemia cells.
January 2011, Retrovirology,
Tomonaga Ichikawa, and Kazuhiro Sugamoto, and Yasushi Matsuura, and Hisato Kunitake, and Kazuya Shimoda, and Kazuhiro Morishita
Organosilicon compounds as adult T-cell leukemia cell proliferation inhibitors.
January 2013, Chemical & pharmaceutical bulletin,
Copied contents to your clipboard!