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

作　　者：Ning Su Yu Fang Xu Chen Xiaoqin Chen Zhongjun Xia Huiqiang Huang Yi Xia Panpan Liu Xiaopeng Tian Qingqing Cai 

机构地区：[1]Department of Medical Oncology,Sun Yat-sen University Cancer Center,Guangzhou,China [2]State Key Laboratory of Oncology in South China,Collaborative Innovation Center of Cancer Medicine,Sun Yat-sen University Cancer Center,Guangzhou,China [3]Department of Oncology,Guangzhou Chest Hospital,Guangzhou,China [4]Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation,Sun Yat-sen Memorial Hospital,Sun Yat-sen University,Guangzhou,China [5]Department of Oncology,Sun Yat-sen Memorial Hospital,Sun Yat-sen University,Guangzhou 510120,China [6]Department of Urology,Sun Yat-sen Memorial Hospital,Sun Yat-sen University,Guangzhou,China [7]Department of Hematology Oncology,Sun Yat-sen University Cancer Center,Guangzhou,China

出　　处：《Blood Science》2023年第4期249-257,共9页血液科学（英文）

基　　金：supported by grants from the National Key Research and Development Program(No.2022YFC2502602 to Dr.Q.C.);the National Natural Science Foundation project(Nos.82230001 and 82270199 to Dr.Q.C.,No.81973384 to Dr.X.T.);the Medical Research Foundation of Guangdong Province(No.A2023488 to Dr.Y.F.).

摘　　要：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.

关 键 词：P21-activated kinase PAK inhibitor PROLIFERATION RELAPSE T-cell lymphoblastic lymphoma 

分 类 号：R733.4[医药卫生—肿瘤]