Cargando…

Targeting P21-activated kinase suppresses proliferation and enhances chemosensitivity in T-cell lymphoblastic lymphoma

T-cell lymphoblastic lymphoma (T-LBL) is a highly aggressive non-Hodgkin lymphoma with a poor prognosis. P21-activated kinase (PAK) is a component of the gene expression-based classifier that can predict the prognosis of T-LBL. However, the role of PAK in T-LBL progression and survival remains poorl...

Descripción completa

Detalles Bibliográficos
Autores principales: Su, Ning, Fang, Yu, Chen, Xu, Chen, Xiaoqin, Xia, Zhongjun, Huang, Huiqiang, Xia, Yi, Liu, Panpan, Tian, Xiaopeng, Cai, Qingqing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10629744/
https://www.ncbi.nlm.nih.gov/pubmed/37941919
http://dx.doi.org/10.1097/BS9.0000000000000169
_version_ 1785132021296660480
author Su, Ning
Fang, Yu
Chen, Xu
Chen, Xiaoqin
Xia, Zhongjun
Huang, Huiqiang
Xia, Yi
Liu, Panpan
Tian, Xiaopeng
Cai, Qingqing
author_facet Su, Ning
Fang, Yu
Chen, Xu
Chen, Xiaoqin
Xia, Zhongjun
Huang, Huiqiang
Xia, Yi
Liu, Panpan
Tian, Xiaopeng
Cai, Qingqing
author_sort Su, Ning
collection PubMed
description T-cell lymphoblastic lymphoma (T-LBL) is a highly aggressive non-Hodgkin lymphoma with a poor prognosis. P21-activated kinase (PAK) is a component of the gene expression-based classifier that can predict the prognosis of T-LBL. However, the role of PAK in T-LBL progression and survival remains poorly understood. Herein, we found that the expression of PAK1 was significantly higher in T-LBL cell lines (Jurkat, SUP-T1, and CCRF-CEM) compared to the human T-lymphoid cell line. Moreover, PAK2 mRNA level of 32 relapsed T-LBL patients was significantly higher than that of 37 cases without relapse (P = .012). T-LBL patients with high PAK1 and PAK2 expression had significantly shorter median RFS than those with low PAK1 and PAK2 expression (PAK1, P = .028; PAK2, P = .027; PAK1/2, P = .032). PAK inhibitors, PF3758309 (PF) and FRAX597, could suppress the proliferation of T-LBL cells by blocking the G1/S cell cycle phase transition. Besides, PF could enhance the chemosensitivity to doxorubicin in vitro and in vivo. Mechanistically, through western blotting and RNA sequencing, we identified that PF could inhibit the phosphorylation of PAK1/2 and downregulate the expression of cyclin D1, NF-κB and cell adhesion signaling pathways in T-LBL cell lines. These findings suggest that PAK might be associated with T-LBL recurrence and further found that PAK inhibitors could suppress proliferation and enhance chemosensitivity of T-LBL cells treated with doxorubicin. Collectively, our present study underscores the potential therapeutic effect of inhibiting PAK in T-LBL therapy.
format Online
Article
Text
id pubmed-10629744
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Lippincott Williams & Wilkins
record_format MEDLINE/PubMed
spelling pubmed-106297442023-11-08 Targeting P21-activated kinase suppresses proliferation and enhances chemosensitivity in T-cell lymphoblastic lymphoma Su, Ning Fang, Yu Chen, Xu Chen, Xiaoqin Xia, Zhongjun Huang, Huiqiang Xia, Yi Liu, Panpan Tian, Xiaopeng Cai, Qingqing Blood Sci Research Articles T-cell lymphoblastic lymphoma (T-LBL) is a highly aggressive non-Hodgkin lymphoma with a poor prognosis. P21-activated kinase (PAK) is a component of the gene expression-based classifier that can predict the prognosis of T-LBL. However, the role of PAK in T-LBL progression and survival remains poorly understood. Herein, we found that the expression of PAK1 was significantly higher in T-LBL cell lines (Jurkat, SUP-T1, and CCRF-CEM) compared to the human T-lymphoid cell line. Moreover, PAK2 mRNA level of 32 relapsed T-LBL patients was significantly higher than that of 37 cases without relapse (P = .012). T-LBL patients with high PAK1 and PAK2 expression had significantly shorter median RFS than those with low PAK1 and PAK2 expression (PAK1, P = .028; PAK2, P = .027; PAK1/2, P = .032). PAK inhibitors, PF3758309 (PF) and FRAX597, could suppress the proliferation of T-LBL cells by blocking the G1/S cell cycle phase transition. Besides, PF could enhance the chemosensitivity to doxorubicin in vitro and in vivo. Mechanistically, through western blotting and RNA sequencing, we identified that PF could inhibit the phosphorylation of PAK1/2 and downregulate the expression of cyclin D1, NF-κB and cell adhesion signaling pathways in T-LBL cell lines. These findings suggest that PAK might be associated with T-LBL recurrence and further found that PAK inhibitors could suppress proliferation and enhance chemosensitivity of T-LBL cells treated with doxorubicin. Collectively, our present study underscores the potential therapeutic effect of inhibiting PAK in T-LBL therapy. Lippincott Williams & Wilkins 2023-07-18 /pmc/articles/PMC10629744/ /pubmed/37941919 http://dx.doi.org/10.1097/BS9.0000000000000169 Text en Copyright © 2023 The Authors. Published by Wolters Kluwer Health Inc., on behalf of the Chinese Medical Association (CMA) and Institute of Hematology, Chinese Academy of Medical Sciences & Peking Union Medical College (IHCAMS). https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) , where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
spellingShingle Research Articles
Su, Ning
Fang, Yu
Chen, Xu
Chen, Xiaoqin
Xia, Zhongjun
Huang, Huiqiang
Xia, Yi
Liu, Panpan
Tian, Xiaopeng
Cai, Qingqing
Targeting P21-activated kinase suppresses proliferation and enhances chemosensitivity in T-cell lymphoblastic lymphoma
title Targeting P21-activated kinase suppresses proliferation and enhances chemosensitivity in T-cell lymphoblastic lymphoma
title_full Targeting P21-activated kinase suppresses proliferation and enhances chemosensitivity in T-cell lymphoblastic lymphoma
title_fullStr Targeting P21-activated kinase suppresses proliferation and enhances chemosensitivity in T-cell lymphoblastic lymphoma
title_full_unstemmed Targeting P21-activated kinase suppresses proliferation and enhances chemosensitivity in T-cell lymphoblastic lymphoma
title_short Targeting P21-activated kinase suppresses proliferation and enhances chemosensitivity in T-cell lymphoblastic lymphoma
title_sort targeting p21-activated kinase suppresses proliferation and enhances chemosensitivity in t-cell lymphoblastic lymphoma
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10629744/
https://www.ncbi.nlm.nih.gov/pubmed/37941919
http://dx.doi.org/10.1097/BS9.0000000000000169
work_keys_str_mv AT suning targetingp21activatedkinasesuppressesproliferationandenhanceschemosensitivityintcelllymphoblasticlymphoma
AT fangyu targetingp21activatedkinasesuppressesproliferationandenhanceschemosensitivityintcelllymphoblasticlymphoma
AT chenxu targetingp21activatedkinasesuppressesproliferationandenhanceschemosensitivityintcelllymphoblasticlymphoma
AT chenxiaoqin targetingp21activatedkinasesuppressesproliferationandenhanceschemosensitivityintcelllymphoblasticlymphoma
AT xiazhongjun targetingp21activatedkinasesuppressesproliferationandenhanceschemosensitivityintcelllymphoblasticlymphoma
AT huanghuiqiang targetingp21activatedkinasesuppressesproliferationandenhanceschemosensitivityintcelllymphoblasticlymphoma
AT xiayi targetingp21activatedkinasesuppressesproliferationandenhanceschemosensitivityintcelllymphoblasticlymphoma
AT liupanpan targetingp21activatedkinasesuppressesproliferationandenhanceschemosensitivityintcelllymphoblasticlymphoma
AT tianxiaopeng targetingp21activatedkinasesuppressesproliferationandenhanceschemosensitivityintcelllymphoblasticlymphoma
AT caiqingqing targetingp21activatedkinasesuppressesproliferationandenhanceschemosensitivityintcelllymphoblasticlymphoma