Rho-kinase: regulation, (dys)function, and inhibition

Amin, Ehsan; Dubey, Badri N.; Zhang, Si-Cai; Gremer, Lothar; Dvorský, Radovan; Moll, Jens M.; Taha, Mohamed S.; Nagel-Steger, Luitgard; Piekorz, Roland P.; Somlyo, Avril V.; Ahmadian, Mohammad Réza

doi:10.1515/hsz-2013-0181

Cited by 157 publications

(144 citation statements)

References 151 publications

(182 reference statements)

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“…Thus, functionally, it activates cell-to-cell adhesion. Finally, in line with the notion that inhibition of Rho-associated kinase, a major effector of RhoA, increases cadherin-mediated adhesion complexes (45), the authors noted that inhibitors of Rho-associated kinase caused a significant increase in b-cell adhesion to recombinant E-cad/Fc (Fig. 1).…”

supporting

confidence: 65%

Cadherins in Islet β-Cells: More Than Meets the Eye

Cirulli

2015

Diabetes

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supporting

confidence: 65%

Cadherins in Islet β-Cells: More Than Meets the Eye

Cirulli

2015

Diabetes

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“…Due to its effects on cell motility, invasion, and angiogenesis (59), as well as effects on tumor stromal cells (60), ROCK has long been considered as a potential target in oncology. The ROCK inhibitors Y-27632 and Fasudil have been used in several cancer studies (32).…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Molecular Pathways: Targeting the Kinase Effectors of RHO-Family GTPases

Prudnikova

Rawat

Chernoff

2015

Clinical Cancer Research

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RHO GTPases, members of the RAS superfamily of small GTPases, are adhesion and growth-factor activated molecular switches that play important roles in tumor development and progression. When activated, RHO-family GTPases such as RAC1, CDC42, and RHOA, transmit signals by recruiting a variety of effector proteins, including the protein kinases PAK, ACK, MLK, MRCK, and ROCK. Genetically-induced loss of RHO function impedes transformation by a number of oncogenic stimuli, leading to an interest in developing small molecule inhibitors that either target RHO GTPases directly, or that target their downstream protein kinase effectors. Although inhibitors of RHO GTPases and their downstream signaling kinases have not yet been widely adopted for clinical use, their potential value as cancer therapeutics continues to facilitate pharmaceutical research and development and is a promising therapeutic strategy.

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“…Members of the Rho subgroup of Ras GTPases, comprising RhoA, RhoB, and RhoC, induce actin cytoskeleton rearrangement and mediate a number of cellular functions (29,30). Although RhoA and RhoB expression levels were not significantly associated with patient clinicopathologic findings, RhoC overexpression has been shown to play a role in tumor invasion and correlates with a poor patient prognosis (31).…”

Section: Discussionmentioning

confidence: 99%

HIF-3α Promotes Metastatic Phenotypes in Pancreatic Cancer by Transcriptional Regulation of the RhoC–ROCK1 Signaling Pathway

Zhou

Guo

Chen

et al. 2018

Molecular Cancer Research

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Hypoxia contributes to pancreatic cancer progression and promotes its growth and invasion. Previous research principally focused on hypoxia-inducible factor-1 alpha (HIF-1a) and HIF2a (HIF1A and EPAS1) as the major hypoxia-associated transcription factors in pancreatic cancer. However, the role of HIF-3a (HIF3A) has not been investigated. Therefore, HIF-1a, HIF-2a, and HIF-3a expression levels were measured under normoxic and hypoxic conditions. In addition, HIF-3a expression was measured in human pancreatic cancer tissue specimens and the impact of altered HIF-3a expression on cell invasion and migration was investigated in vitro and in vivo, as well as the underlying mechanisms. Under hypoxic conditions, HIF-3a expression was stimulated in pancreatic cancer cells to a greater degree than HIF-1a and HIF-2a expression. HIF-3a protein levels were also elevated in pancreatic cancer tissues and correlated with reduced survival and greater local invasion and distant metastasis, whereas knockdown of HIF-3a, under hypoxic conditions, suppressed pancreatic cancer cell invasion and migration. Under normoxia, HIF-3a overexpression promoted pancreatic cancer cell invasion and migration and stimulated F-actin polymerization. In summary, HIF-3a promotes pancreatic cancer cell invasion and metastasis in vivo and promotes pancreatic cancer cell invasion and metastasis by transcriptionally activating the RhoC-ROCK1 signaling pathway.Implications: HIF3a is overexpressed in pancreatic cancer, and targeting the HIF3a/RhoC-ROCK1 signaling pathway may be a novel therapeutic approach for the treatment of pancreatic cancer invasion and metastasis.

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Rho-kinase: regulation, (dys)function, and inhibition

Cited by 157 publications

References 151 publications

Cadherins in Islet β-Cells: More Than Meets the Eye

Cadherins in Islet β-Cells: More Than Meets the Eye

Molecular Pathways: Targeting the Kinase Effectors of RHO-Family GTPases

HIF-3α Promotes Metastatic Phenotypes in Pancreatic Cancer by Transcriptional Regulation of the RhoC–ROCK1 Signaling Pathway

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