Targeting the cyclin-dependent kinase 5 in metastatic melanoma

被引：19

作者：

Sharma, Samanta ^{[1
,2
]}

Zhang, Tian ^{[3
]}

Michowski, Wojciech ^{[1
,2
]}

Rebecca, Vito W. ^{[4
]}

Xiao, Min ^{[4
]}

Ferretti, Roberta ^{[5
,6
]}

Suski, Jan M. ^{[1
,2
]}

Bronson, Roderick T. ^{[7
]}

Paulo, Joao A. ^{[3
]}

Frederick, Dennie ^{[8
]}

Fassl, Anne ^{[1
,2
]}

Boland, Genevieve M. ^{[8
]}

Geng, Yan ^{[1
,2
]}

Lees, Jacqueline A. ^{[5
,9
]}

Medema, Rene H. ^{[10
]}

Herlyn, Meenhard ^{[4
]}

Gygi, Steven P. ^{[3
]}

Sicinski, Piotr ^{[1
,2
]}

机构：

[1] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA

[2] Harvard Med Sch, Blavatnik Inst, Dept Genet, Boston, MA 02115 USA

[3] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA

[4] Wistar Inst Anat & Biol, Oncogenesis Program, Philadelphia, PA 19104 USA

[5] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA

[6] Emmanuel Merck Darmstadt EMD Serono Res & Dev Inc, Translat Innovat Platform Oncol, Billerica, MA 01821 USA

[7] Harvard Med Sch, Rodent Histopathol Core, Boston, MA 02115 USA

[8] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA

[9] MIT, Dept Biol, Cambridge, MA 02139 USA

[10] Netherlands Canc Inst, Oncode Inst, Div Cell Biol, NL-1066 CX Amsterdam, Netherlands

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2020年 / 117卷 / 14期

关键词：

cyclin-dependent kinases; CDK5; metastasis; mouse cancer models; INTERMEDIATE-FILAMENT REORGANIZATION; UNNATURAL NUCLEOTIDE SPECIFICITY; CELL-CYCLE; PANCREATIC-CANCER; CDK5; PHOSPHORYLATION; VIMENTIN; EXPRESSION; PROTEIN; DISRUPTION;

D O I：

10.1073/pnas.1912617117

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The cyclin-dependent kinase 5 (CDK5), originally described as a neuronal-specific kinase, is also frequently activated in human cancers. Using conditional CDK5 knockout mice and a mouse model of highly metastatic melanoma, we found that CDK5 is dispensable for the growth of primary tumors. However, we observed that ablation of CDK5 completely abrogated the metastasis, revealing that CDK5 is essential for the metastatic spread. In mouse and human melanoma cells CDK5 promotes cell invasiveness by directly phosphorylating an intermediate filament protein, vimentin, thereby inhibiting assembly of vimentin filaments. Chemical inhibition of CDK5 blocks the metastatic spread of patient-derived melanomas in patient-derived xenograft (PDX) mouse models. Hence, inhibition of CDK5 might represent a very potent therapeutic strategy to impede the metastatic dissemination of malignant cells.

引用

页码：8001 / 8012

页数：12

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