Rho GTPases: Anti- or pro-neoplastic targets?

被引:73
作者
Zandvakili, I. [1 ,2 ,3 ]
Lin, Y. [1 ]
Morris, J. C. [4 ]
Zheng, Y. [1 ,2 ,3 ]
机构
[1] Cincinnati Childrens Hosp Med Ctr, Expt Hematol & Canc Biol, 3333 Burnet Ave, Cincinnati, OH 45229 USA
[2] Cincinnati Childrens Hosp Med Ctr, Mol & Dev Biol Grad Program, Cincinnati, OH 45229 USA
[3] Univ Cincinnati, Coll Med, Med Scientist Training Program, Cincinnati, OH USA
[4] Univ Cincinnati, Dept Internal Med, Div Hematol Oncol, Cincinnati, OH USA
关键词
CANCER-CELL MOTILITY; DRIVER MUTATIONS; RATIONAL DESIGN; TUMOR-FORMATION; PROTEIN-KINASE; BREAST-CANCER; LUNG-CANCER; PERINEURAL INVASION; PROTEOMIC ANALYSIS; SIGNALING AXIS;
D O I
10.1038/onc.2016.473
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Rho GTPases are critical signal transducers of multiple pathways. They have been proposed to be useful anti-neoplastic targets for over two decades, especially in Ras-driven cancers. Until recently, however, few in vivo studies had been carried out to test this premise. Several recent mouse model studies have verified that Rac1, RhoA, and some of their effector proteins such as PAK and ROCK, are likely anti-cancer targets for treating K-Ras-driven tumours. Other seemingly contradictory studies have suggested that at least in certain instances inhibition of individual Rho GTPases may paradoxically result in pro-neoplastic effects. Significantly, both RhoA GTPase gain-and loss-of-function mutations have been discovered in primary leukemia/lymphoma and gastric cancer by human cancer genome sequencing efforts, suggesting both pro-and anti-neoplastic roles. In this review we summarize and integrate these unexpected findings and discuss the mechanistic implications in the design and application of Rho GTPase targeting strategies in future cancer therapies.
引用
收藏
页码:3213 / 3222
页数:10
相关论文
共 162 条
[51]   Mechanism and consequences of RAF kinase activation by small-molecule inhibitors [J].
Holderfield, M. ;
Nagel, T. E. ;
Stuart, D. D. .
BRITISH JOURNAL OF CANCER, 2014, 111 (04) :640-645
[52]  
Hu LD, 2007, ONCOL REP, V17, P1383
[53]  
Huang M, 2006, HISTOL HISTOPATHOL, V21, P213, DOI 10.14670/HH-21.213
[54]   Crystal structure of human RhoA in a dominantly active form complexed with a GTP analogue [J].
Ihara, K ;
Muraguchi, S ;
Kato, M ;
Shimizu, T ;
Shirakawa, M ;
Kuroda, S ;
Kaibuchi, K ;
Hakoshima, T .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (16) :9656-9666
[55]   Mapping the Hallmarks of Lung Adenocarcinoma with Massively Parallel Sequencing [J].
Imielinski, Marcin ;
Berger, Alice H. ;
Hammerman, Peter S. ;
Hernandez, Bryan ;
Pugh, Trevor J. ;
Hodis, Eran ;
Cho, Jeonghee ;
Suh, James ;
Capelletti, Marzia ;
Sivachenko, Andrey ;
Sougnez, Carrie ;
Auclair, Daniel ;
Lawrence, Michael S. ;
Stojanov, Petar ;
Cibulskis, Kristian ;
Choi, Kyusam ;
de Waal, Luc ;
Sharifnia, Tanaz ;
Brooks, Angela ;
Greulich, Heidi ;
Banerji, Shantanu ;
Zander, Thomas ;
Seidel, Danila ;
Leenders, Frauke ;
Ansen, Sascha ;
Ludwig, Corinna ;
Engel-Riedel, Walburga ;
Stoelben, Erich ;
Wolf, Juergen ;
Goparju, Chandra ;
Thompson, Kristin ;
Winckler, Wendy ;
Kwiatkowski, David ;
Johnson, Bruce E. ;
Jaenne, Pasi A. ;
Miller, Vincent A. ;
Pao, William ;
Travis, William D. ;
Pass, Harvey I. ;
Gabriel, Stacey B. ;
Lander, Eric S. ;
Thomas, Roman K. ;
Garraway, Levi A. ;
Getz, Gad ;
Meyerson, Matthew .
CELL, 2012, 150 (06) :1107-1120
[56]   Opposite RHOA functions within the ATLL category [J].
Ishikawa, Shumpei .
BLOOD, 2016, 127 (05) :524-525
[57]  
Jiang WG, 2003, CLIN CANCER RES, V9, P6432
[58]  
Jones MB, 2002, PROTEOMICS, V2, P76, DOI 10.1002/1615-9861(200201)2:1<76::AID-PROT76>3.3.CO
[59]  
2-F
[60]   Cloning of a novel human Rac1b splice variant with increased expression in colorectal tumors [J].
Jordan, P ;
Brazao, R ;
Boavida, MG ;
Gespach, C ;
Chastre, E .
ONCOGENE, 1999, 18 (48) :6835-6839