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Rho-associated kinase signalling and the cancer microenvironment: novel biological implications and therapeutic opportunities.

Chin VT, Nagrial AM, Chou A, Biankin AV, Gill AJ, Timpson P, Pajic M - Expert Rev Mol Med (2015)

Bottom Line: Their performance as an anti-cancer therapy has been varied in pre-clinical studies, however, they have been shown to be effective vasodilators in the treatment of hypertension and post-ischaemic stroke vasospasm.This review addresses the various roles the Rho/ROCK pathway plays in angiogenesis, tumour vascular tone and reciprocal feedback from the tumour microenvironment and explores the potential utility of ROCK inhibitors as effective vascular normalising agents.ROCK inhibitors may potentially enhance the delivery and efficacy of chemotherapy agents and improve the effectiveness of radiotherapy.

View Article: PubMed Central - PubMed

Affiliation: The Kinghorn Cancer Centre,Cancer Division,Garvan Institute of Medical Research,384 Victoria St,Darlinghurst,Sydney,NSW 2010,Australia.

ABSTRACT
The Rho/ROCK pathway is involved in numerous pivotal cellular processes that have made it an area of intense study in cancer medicine, however, Rho-associated coiled-coil containing protein kinase (ROCK) inhibitors are yet to make an appearance in the clinical cancer setting. Their performance as an anti-cancer therapy has been varied in pre-clinical studies, however, they have been shown to be effective vasodilators in the treatment of hypertension and post-ischaemic stroke vasospasm. This review addresses the various roles the Rho/ROCK pathway plays in angiogenesis, tumour vascular tone and reciprocal feedback from the tumour microenvironment and explores the potential utility of ROCK inhibitors as effective vascular normalising agents. ROCK inhibitors may potentially enhance the delivery and efficacy of chemotherapy agents and improve the effectiveness of radiotherapy. As such, repurposing of these agents as adjuncts to standard treatments may significantly improve outcomes for patients with cancer. A deeper understanding of the controlled and dynamic regulation of the key components of the Rho pathway may lead to effective use of the Rho/ROCK inhibitors in the clinical management of cancer.

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Key components of the Rho/ Rho-associated coiled-coil containing protein kinase (ROCK) signalling pathway. Various extracellular stimuli (growth factors and hormones) bind to cell membrane receptors, which subsequently act upon guanine-nucleotide-exchange factors (GEFs) and GTPase-activating proteins (GAPs) to regulate activation of Rho GTPase proteins. Once in its GTP-bound ‘active’ state, Rho GTPase binds to ROCK (ROCK1/2) to stimulate key downstream effectors (Refs 7, 12, 21). ROCK-mediated phosphorylation of myosin light-chain (MLC) promotes phosphorylation of myosin and increased actomyosin contraction. Activation of LIMK by ROCK leads to phosphorylation and inactivation of the actin-depolymerising protein cofilin, altering actin filament organisation. Collectively, activation of key downstream effectors of Rho causes changes in motility, proliferation and other essential cellular processes.
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fig01: Key components of the Rho/ Rho-associated coiled-coil containing protein kinase (ROCK) signalling pathway. Various extracellular stimuli (growth factors and hormones) bind to cell membrane receptors, which subsequently act upon guanine-nucleotide-exchange factors (GEFs) and GTPase-activating proteins (GAPs) to regulate activation of Rho GTPase proteins. Once in its GTP-bound ‘active’ state, Rho GTPase binds to ROCK (ROCK1/2) to stimulate key downstream effectors (Refs 7, 12, 21). ROCK-mediated phosphorylation of myosin light-chain (MLC) promotes phosphorylation of myosin and increased actomyosin contraction. Activation of LIMK by ROCK leads to phosphorylation and inactivation of the actin-depolymerising protein cofilin, altering actin filament organisation. Collectively, activation of key downstream effectors of Rho causes changes in motility, proliferation and other essential cellular processes.

Mentions: The Rho family of small GTPases regulate a diverse array of cellular processes, including cytoskeletal dynamics, cell polarity, membrane transport and gene expression, which are integral for the growth and metastatic potential of cancer cells (Ref. 7). The three best characterised members of this family are Rho (A, B and C), Rac (1, 2 and 3) and Cdc42 (Ref. 7). They cycle between a GTP-bound active state and GDP-bound inactive state which is mediated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), as illustrated in Figure 1 (Refs 12, 13). In their active state, they act on one of over 60 downstream targets which include Rho-associated coiled-coil containing protein kinase (ROCK), mDia (Ref. 14), serine/threonine p21-activating kinases 4-6 (Ref. 15), Par6 (Ref. 16) and Wiskott-Aldrich Syndrome Protein (Ref. 17). In addition, through interaction with various well characterised pathways, including the phosphoinositide 3-kinase, focal adhesion kinase, Src, LIM domain kinase (LIMK) and mitogen-activated protein kinase/Erk protein networks, Rho GTPase activation ultimately leads to actin cytoskeleton remodelling, increased cell motility, changes in proliferation and cell survival (Refs 10, 18, 19, 20). ROCK, a downstream effector of Rho, phosphorylates MYPT1, the targeting subunit of myosin phosphatase, resulting in decreased myosin phosphatase activity and thereby increased phosphorylation of the regulatory myosin light-chain 2 (MLC2) protein (Ref. 21). Both ROCK/MYPT1/MLC2 and ROCK/LIMK/cofilin signalling axes are heavily involved in stress fibre assembly, cell adhesion and motility (Fig. 1). Further, the ROCK family contains two members, ROCK1 and ROCK2, which share 65% overall identity and 92% identity in the kinase domain (Ref. 22) and are thus believed to also share more than 30 immediate downstream substrates, including MYPT1, MLC, and LIMK (Ref. 7). Some differences in the activation of specific isoforms of ROCK have also been reported. For example, induction of pressure overload cardiac hypertrophy in mice leads to elevated ROCK1, but not ROCK2, expression (Ref. 22) and specific activation of the Rho/ROCK1/c-Jun N-terminal kinase (JNK) signalling in hypertrophic cardiomyocytes (Ref. 23). Similarly, ROCK2 has been implicated as the relevant isoform in a mouse model of acute ischaemic stroke (Ref. 24). Finally, emerging evidence suggests potential distinct roles of ROCK1 and ROCK2 in regulating stress-induced actin cytoskeleton reorganisation and cell detachment in mouse embryonic fibroblasts (Ref. 25) and migrating neurons (Ref. 26).Figure 1.


Rho-associated kinase signalling and the cancer microenvironment: novel biological implications and therapeutic opportunities.

Chin VT, Nagrial AM, Chou A, Biankin AV, Gill AJ, Timpson P, Pajic M - Expert Rev Mol Med (2015)

Key components of the Rho/ Rho-associated coiled-coil containing protein kinase (ROCK) signalling pathway. Various extracellular stimuli (growth factors and hormones) bind to cell membrane receptors, which subsequently act upon guanine-nucleotide-exchange factors (GEFs) and GTPase-activating proteins (GAPs) to regulate activation of Rho GTPase proteins. Once in its GTP-bound ‘active’ state, Rho GTPase binds to ROCK (ROCK1/2) to stimulate key downstream effectors (Refs 7, 12, 21). ROCK-mediated phosphorylation of myosin light-chain (MLC) promotes phosphorylation of myosin and increased actomyosin contraction. Activation of LIMK by ROCK leads to phosphorylation and inactivation of the actin-depolymerising protein cofilin, altering actin filament organisation. Collectively, activation of key downstream effectors of Rho causes changes in motility, proliferation and other essential cellular processes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4836205&req=5

fig01: Key components of the Rho/ Rho-associated coiled-coil containing protein kinase (ROCK) signalling pathway. Various extracellular stimuli (growth factors and hormones) bind to cell membrane receptors, which subsequently act upon guanine-nucleotide-exchange factors (GEFs) and GTPase-activating proteins (GAPs) to regulate activation of Rho GTPase proteins. Once in its GTP-bound ‘active’ state, Rho GTPase binds to ROCK (ROCK1/2) to stimulate key downstream effectors (Refs 7, 12, 21). ROCK-mediated phosphorylation of myosin light-chain (MLC) promotes phosphorylation of myosin and increased actomyosin contraction. Activation of LIMK by ROCK leads to phosphorylation and inactivation of the actin-depolymerising protein cofilin, altering actin filament organisation. Collectively, activation of key downstream effectors of Rho causes changes in motility, proliferation and other essential cellular processes.
Mentions: The Rho family of small GTPases regulate a diverse array of cellular processes, including cytoskeletal dynamics, cell polarity, membrane transport and gene expression, which are integral for the growth and metastatic potential of cancer cells (Ref. 7). The three best characterised members of this family are Rho (A, B and C), Rac (1, 2 and 3) and Cdc42 (Ref. 7). They cycle between a GTP-bound active state and GDP-bound inactive state which is mediated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), as illustrated in Figure 1 (Refs 12, 13). In their active state, they act on one of over 60 downstream targets which include Rho-associated coiled-coil containing protein kinase (ROCK), mDia (Ref. 14), serine/threonine p21-activating kinases 4-6 (Ref. 15), Par6 (Ref. 16) and Wiskott-Aldrich Syndrome Protein (Ref. 17). In addition, through interaction with various well characterised pathways, including the phosphoinositide 3-kinase, focal adhesion kinase, Src, LIM domain kinase (LIMK) and mitogen-activated protein kinase/Erk protein networks, Rho GTPase activation ultimately leads to actin cytoskeleton remodelling, increased cell motility, changes in proliferation and cell survival (Refs 10, 18, 19, 20). ROCK, a downstream effector of Rho, phosphorylates MYPT1, the targeting subunit of myosin phosphatase, resulting in decreased myosin phosphatase activity and thereby increased phosphorylation of the regulatory myosin light-chain 2 (MLC2) protein (Ref. 21). Both ROCK/MYPT1/MLC2 and ROCK/LIMK/cofilin signalling axes are heavily involved in stress fibre assembly, cell adhesion and motility (Fig. 1). Further, the ROCK family contains two members, ROCK1 and ROCK2, which share 65% overall identity and 92% identity in the kinase domain (Ref. 22) and are thus believed to also share more than 30 immediate downstream substrates, including MYPT1, MLC, and LIMK (Ref. 7). Some differences in the activation of specific isoforms of ROCK have also been reported. For example, induction of pressure overload cardiac hypertrophy in mice leads to elevated ROCK1, but not ROCK2, expression (Ref. 22) and specific activation of the Rho/ROCK1/c-Jun N-terminal kinase (JNK) signalling in hypertrophic cardiomyocytes (Ref. 23). Similarly, ROCK2 has been implicated as the relevant isoform in a mouse model of acute ischaemic stroke (Ref. 24). Finally, emerging evidence suggests potential distinct roles of ROCK1 and ROCK2 in regulating stress-induced actin cytoskeleton reorganisation and cell detachment in mouse embryonic fibroblasts (Ref. 25) and migrating neurons (Ref. 26).Figure 1.

Bottom Line: Their performance as an anti-cancer therapy has been varied in pre-clinical studies, however, they have been shown to be effective vasodilators in the treatment of hypertension and post-ischaemic stroke vasospasm.This review addresses the various roles the Rho/ROCK pathway plays in angiogenesis, tumour vascular tone and reciprocal feedback from the tumour microenvironment and explores the potential utility of ROCK inhibitors as effective vascular normalising agents.ROCK inhibitors may potentially enhance the delivery and efficacy of chemotherapy agents and improve the effectiveness of radiotherapy.

View Article: PubMed Central - PubMed

Affiliation: The Kinghorn Cancer Centre,Cancer Division,Garvan Institute of Medical Research,384 Victoria St,Darlinghurst,Sydney,NSW 2010,Australia.

ABSTRACT
The Rho/ROCK pathway is involved in numerous pivotal cellular processes that have made it an area of intense study in cancer medicine, however, Rho-associated coiled-coil containing protein kinase (ROCK) inhibitors are yet to make an appearance in the clinical cancer setting. Their performance as an anti-cancer therapy has been varied in pre-clinical studies, however, they have been shown to be effective vasodilators in the treatment of hypertension and post-ischaemic stroke vasospasm. This review addresses the various roles the Rho/ROCK pathway plays in angiogenesis, tumour vascular tone and reciprocal feedback from the tumour microenvironment and explores the potential utility of ROCK inhibitors as effective vascular normalising agents. ROCK inhibitors may potentially enhance the delivery and efficacy of chemotherapy agents and improve the effectiveness of radiotherapy. As such, repurposing of these agents as adjuncts to standard treatments may significantly improve outcomes for patients with cancer. A deeper understanding of the controlled and dynamic regulation of the key components of the Rho pathway may lead to effective use of the Rho/ROCK inhibitors in the clinical management of cancer.

Show MeSH
Related in: MedlinePlus