抗肿瘤药物:PBK/TOPK抑制剂的研究进展
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摘要
PBK/TOPK是一种丝-苏氨酸蛋白激酶,正常生理情况下,TOPK仅在睾丸和胸腺中表达。近年来研究表明,TOPK在多种恶性肿瘤细胞中呈高表达,调控肿瘤细胞的细胞周期,与肿瘤细胞的增殖、侵袭、转移、抗凋亡过程相关。因此,TOPK成为肿瘤治疗的一个靶标,其特异性抑制剂正在研究当中。目前,使用最多的TOPK抑制剂均能与TOPK分子活性中心结合,直接抑制TOPK的功能,从而达到抑制效果。本文综述了TOPK的结构和功能,以及现用于研究的TOPK抑制剂的抗肿瘤作用。
TOPK(T-lymphokine-active killer cell-originated protein kinase) is a Ser/Thr protein kinase. TOPK is seldom expressed in normal tissues, except thymus and testis in physiological conditions. Recent studies have showed that TOPK is up-regulated in varieties of malignant cells, regulating cell cycles. And it relates to the proliferation, invasion, metastasis and anti-apoptosis effect of tumor cells. Therefor, TOPK has become a valuable therapeutic target. Its specific inhibitors are now under research. TOPK inhibitors which are under studying can bind with the active center of the TOPK molecule, and they can directly inhibit the function of TOPK. This article reviews the construction and function of TOPK as well as the effect of TOPK inhibitor on oncotherapy.
TOPK(T-lymphokine-active killer cell-originated protein kinase) is a Ser/Thr protein kinase. TOPK is seldom expressed in normal tissues, except thymus and testis in physiological conditions. Recent studies have showed that TOPK is up-regulated in varieties of malignant cells, regulating cell cycles. And it relates to the proliferation, invasion, metastasis and anti-apoptosis effect of tumor cells. Therefor, TOPK has become a valuable therapeutic target. Its specific inhibitors are now under research. TOPK inhibitors which are under studying can bind with the active center of the TOPK molecule, and they can directly inhibit the function of TOPK. This article reviews the construction and function of TOPK as well as the effect of TOPK inhibitor on oncotherapy.
引文
[1]Abe Y,Matsumoto S,Kito K,et al.Expression of a novel MAPKK-like protein kinase,lymphokine-activated killer T-cell-originated protein kinase,specifically expressed in the testis and activated lymphoid cells.J Biol Chem,2000,275(28):21525-21531
[2]Gaudet S,Branton D,Lue RA.Characterization of PDZ-binding kinase,a mitotic kinase.Proc Natl Acad Sci USA,2000,97(10):5167-5172
[3]Kirubakaran P,Karthikeyan M,Singh KD,et al.In silico structural and functional analysis of the human TOPKprotein by structure modeling and molecular dynamics studies.J Mol Model,2013,19(1):407-419
[4]Matsumoto S,Abe Y,Fujibuchi T,et al.Characterization of a MAPKK-like protein kinase TOPK.Biochem Biophys Res Commun,2004,17,325(3):997-1004
[5]Abe Y,Takeuchi T,Kagawa-Miki L,et al.A mitotic kinase TOPK enhances Cdk1/cyclin B1-dependent phosphorylation of PRC1 and promotes cytokinesis.J Mol Biol,2007,370(2):231-245
[6]Matsuo Y,Park JH,Miyamoto T,et al.TOPK inhibitor induces complete tumor regression in xenograft models of human cancer through inhibition of cytokinesis.Sci Transl Med,2014,6(259):259-245
[7]Ikeda Y,Park JH,Miyamoto T,et al.T-LAK cell-originated protein kinase(TOPK)as a prognostic factor and a potential therapeutic target in ovarian cancer.Clin Cancer Res,2016,22(24):6110-6117
[8]Zhu F,Zykova TA,Abe Y,et al.Bidirectional signals transduced by TOPK-ERK interaction increase tumorigenesis of HCT116 colorectal cancer cells.Gastroenterology,2007,133:219-231
[9]Simons-Evelyn M,Bailey-Dell K,Toretsky JA,et al.PBK/TOPK is a novel mitotic kinase which is upregulated in Burkitt's lymphoma and other highly proliferative malignant cells.Blood Cells Mol Dis,2001,27:825-829
[10]He F,Yan Q,Fan L,Liu Y,Cui J,Wang J,et al.PBK/TOPK in the differential diagnosis of cholangiocarcinoma from hepatocellular carcinoma and its involvement in prognosis of human cholangiocarcinoma.Hum Pathol,2010,41:415-424
[11]Park JH,Nishidate T,Nakamura Y,et al.Critical roles of T-LAK cell-originated protein kinase in cytokinesis.Cancer Sci,2010,101:403-411
[12]Ayllón V,O'connor R.PBK/TOPK promotes tumour cell proliferation through p38 MAPK activity and regulation of the DNA damage response.Oncogene,2007,26:3451-3461
[13]Zhu F,Zykova TA,Kang BS,et al.Bidirectional signals transduced by TOPK-ERK interaction increase tumorigenesis of HCT116 colorectal cancer cells.Gastroenterology,2007,133:219-233
[14]Oh SM,Zhu F,Cho YY,et al.T-Lymphokine-activated killer cell-originated protein kinase functions as a positive regulator of c-Jun-NH2-kinase 1 signaling and H-Ras-induced cell transformation.Cancer Res,2007,67(11):5186-5194
[15]Seol MA,Park JH1,Jeong JH,et al.Role of TOPK in lipopolysaccharide-induced breast cancer cell migration and invasion.Oncotarget,2017,8:40190-40203
[16]Hu F,Gartenhaus RB,Eichberg D,et al.PBK/TOPKinteracts with the DBD domain of tumor suppressor p53and modulates expression of transcriptional targets including p21.Oncogene,2010,29(40):5464-5474
[17]Shih MC,Chen JY,Wu YC,et al.TOPK/PBK promotes cell migration via modulation of the PI3K/PTEN/AKTpathway and is associated with poor prognosis in lung cancer.Oncogene,2012,31(19):2389-2400
[18]Aksamitiene E,Kholodenko BN,Kolch W,et al.PI3K/Akt-sensitive MEK-independent compensatory circuit of ERK activation in ER-positive PI3K-mutant T47D breast cancer cells.Cell Signal,2010,22(9):1369-1378
[19]Kim DJ,Li Y,Reddy K,et al.Novel TOPK inhibitor HI-TOPK-032 effectively suppresses colon cancer growth.Cancer Res,2012,72(12):3060-3068
[20]Wang MY,Lin ZR,Cao Y,et al.PDZ binding kinase(PBK)is a theranostic target for nasopharyngeal carcinoma:driving tumor growth via ROS signaling and correlating with patient survival.Oncotarget,2016,7(18):26604-26616
[21]Joel M,Mughal AA,Grieg Z,et al.Targeting PBK/TOPK decreases growth and survival of glioma initiating cells in vitro and attenuates tumor growth in vivo.Mol Cancer,2015,14:121
[22]Alachkar H,Mutonga M,Malnassy G,et al.T-LAKcell-originated protein kinase presents a novel therapeutic target in FLT3-ITD mutated acute myeloid leukemia.Oncotarget,2015,6:33410-33425
[23]Park JH,Inoue H,Kato T,et al.TOPK(T-LAK cell-originated protein kinase)inhibitor exhibits growth suppressive effect on small cell lung cancer.Cancer Sci,2017,108(3):488-496
[24]Ikeda Y,Park JH,Miyamoto T,et al.T-LAK cell-originated protein kinase(TOPK)as a prognostic factor and a potential therapeutic target in ovarian cancer.Clin Cancer Res,2016,22(24):6110-6117
[25]Kato T,Inoue H,Imoto S,et al.Oncogenic roles of TOPK and MELK,and effective growth suppression by small molecular inhibitors in kidney cancer cells.Oncotarget,2016,7(14):17652-17664
[26]Zeng X,Liu L,Zheng M,et al.Pantoprazole an FDA-approved proton-pump inhibitor,suppresses colorectal cancer growth by targeting T-cell-originated protein kinase.Oncotarget,2016,7(16):22460-22473
[27]Zheng M,Luan S,Gao S,et al.Proton pump inhibitor ilaprazole suppresses cancer growth by targeting T-cell-originated protein kinase.Oncotarget,2017,8:39143-39153
[2]Gaudet S,Branton D,Lue RA.Characterization of PDZ-binding kinase,a mitotic kinase.Proc Natl Acad Sci USA,2000,97(10):5167-5172
[3]Kirubakaran P,Karthikeyan M,Singh KD,et al.In silico structural and functional analysis of the human TOPKprotein by structure modeling and molecular dynamics studies.J Mol Model,2013,19(1):407-419
[4]Matsumoto S,Abe Y,Fujibuchi T,et al.Characterization of a MAPKK-like protein kinase TOPK.Biochem Biophys Res Commun,2004,17,325(3):997-1004
[5]Abe Y,Takeuchi T,Kagawa-Miki L,et al.A mitotic kinase TOPK enhances Cdk1/cyclin B1-dependent phosphorylation of PRC1 and promotes cytokinesis.J Mol Biol,2007,370(2):231-245
[6]Matsuo Y,Park JH,Miyamoto T,et al.TOPK inhibitor induces complete tumor regression in xenograft models of human cancer through inhibition of cytokinesis.Sci Transl Med,2014,6(259):259-245
[7]Ikeda Y,Park JH,Miyamoto T,et al.T-LAK cell-originated protein kinase(TOPK)as a prognostic factor and a potential therapeutic target in ovarian cancer.Clin Cancer Res,2016,22(24):6110-6117
[8]Zhu F,Zykova TA,Abe Y,et al.Bidirectional signals transduced by TOPK-ERK interaction increase tumorigenesis of HCT116 colorectal cancer cells.Gastroenterology,2007,133:219-231
[9]Simons-Evelyn M,Bailey-Dell K,Toretsky JA,et al.PBK/TOPK is a novel mitotic kinase which is upregulated in Burkitt's lymphoma and other highly proliferative malignant cells.Blood Cells Mol Dis,2001,27:825-829
[10]He F,Yan Q,Fan L,Liu Y,Cui J,Wang J,et al.PBK/TOPK in the differential diagnosis of cholangiocarcinoma from hepatocellular carcinoma and its involvement in prognosis of human cholangiocarcinoma.Hum Pathol,2010,41:415-424
[11]Park JH,Nishidate T,Nakamura Y,et al.Critical roles of T-LAK cell-originated protein kinase in cytokinesis.Cancer Sci,2010,101:403-411
[12]Ayllón V,O'connor R.PBK/TOPK promotes tumour cell proliferation through p38 MAPK activity and regulation of the DNA damage response.Oncogene,2007,26:3451-3461
[13]Zhu F,Zykova TA,Kang BS,et al.Bidirectional signals transduced by TOPK-ERK interaction increase tumorigenesis of HCT116 colorectal cancer cells.Gastroenterology,2007,133:219-233
[14]Oh SM,Zhu F,Cho YY,et al.T-Lymphokine-activated killer cell-originated protein kinase functions as a positive regulator of c-Jun-NH2-kinase 1 signaling and H-Ras-induced cell transformation.Cancer Res,2007,67(11):5186-5194
[15]Seol MA,Park JH1,Jeong JH,et al.Role of TOPK in lipopolysaccharide-induced breast cancer cell migration and invasion.Oncotarget,2017,8:40190-40203
[16]Hu F,Gartenhaus RB,Eichberg D,et al.PBK/TOPKinteracts with the DBD domain of tumor suppressor p53and modulates expression of transcriptional targets including p21.Oncogene,2010,29(40):5464-5474
[17]Shih MC,Chen JY,Wu YC,et al.TOPK/PBK promotes cell migration via modulation of the PI3K/PTEN/AKTpathway and is associated with poor prognosis in lung cancer.Oncogene,2012,31(19):2389-2400
[18]Aksamitiene E,Kholodenko BN,Kolch W,et al.PI3K/Akt-sensitive MEK-independent compensatory circuit of ERK activation in ER-positive PI3K-mutant T47D breast cancer cells.Cell Signal,2010,22(9):1369-1378
[19]Kim DJ,Li Y,Reddy K,et al.Novel TOPK inhibitor HI-TOPK-032 effectively suppresses colon cancer growth.Cancer Res,2012,72(12):3060-3068
[20]Wang MY,Lin ZR,Cao Y,et al.PDZ binding kinase(PBK)is a theranostic target for nasopharyngeal carcinoma:driving tumor growth via ROS signaling and correlating with patient survival.Oncotarget,2016,7(18):26604-26616
[21]Joel M,Mughal AA,Grieg Z,et al.Targeting PBK/TOPK decreases growth and survival of glioma initiating cells in vitro and attenuates tumor growth in vivo.Mol Cancer,2015,14:121
[22]Alachkar H,Mutonga M,Malnassy G,et al.T-LAKcell-originated protein kinase presents a novel therapeutic target in FLT3-ITD mutated acute myeloid leukemia.Oncotarget,2015,6:33410-33425
[23]Park JH,Inoue H,Kato T,et al.TOPK(T-LAK cell-originated protein kinase)inhibitor exhibits growth suppressive effect on small cell lung cancer.Cancer Sci,2017,108(3):488-496
[24]Ikeda Y,Park JH,Miyamoto T,et al.T-LAK cell-originated protein kinase(TOPK)as a prognostic factor and a potential therapeutic target in ovarian cancer.Clin Cancer Res,2016,22(24):6110-6117
[25]Kato T,Inoue H,Imoto S,et al.Oncogenic roles of TOPK and MELK,and effective growth suppression by small molecular inhibitors in kidney cancer cells.Oncotarget,2016,7(14):17652-17664
[26]Zeng X,Liu L,Zheng M,et al.Pantoprazole an FDA-approved proton-pump inhibitor,suppresses colorectal cancer growth by targeting T-cell-originated protein kinase.Oncotarget,2016,7(16):22460-22473
[27]Zheng M,Luan S,Gao S,et al.Proton pump inhibitor ilaprazole suppresses cancer growth by targeting T-cell-originated protein kinase.Oncotarget,2017,8:39143-39153