Should we keep rocking? Portraits from targeting Rho kinases in cancer

Sousa, Graziella Ribeiro de; Vieira, Gabriela Maciel; Chagas, Pablo Ferreira das; Pezuk, Julia Alejandra; Brassesco, María Sol

doi:10.1016/j.phrs.2020.105093

Cited by 22 publications

(22 citation statements)

References 249 publications

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“…Hundreds of ROCK1 inhibitors have been identi ed and have various therapeutic potentials. ROCK1/2 inhibitors such as fasudil [38,39], AT13148 [40][41][42], Y-27632 [43], YM529/ONO-5920 [44,45], , WF-536 [47][48][49] and RKI-1447 [50] have shown signi cant cancer inhibition [11].…”

Section: Discussionmentioning

confidence: 99%

“…Dasabuvir can combine with other direct-acting antiviral drugs to achieve high cure rates in a variety of interferon-free regiments and low adverse reactions as a nonnucleoside NS5B polymerase inhibitor[8-10]. ROCK1 (Rho-associated coiled-coil kinases 1) is a classical serine-threonine kinase which could regulate the cytoskeleton through phosphorylating the downstream substrates and increasing the stability of actin lament and generation of actomyosin contractility [11]. ROCK1 plays an important role in regulating cell movement, angiogenesis, and migration, and can promote the growth, proliferation, and survival of tumor cells by regulating the tumor microenvironment [12].…”

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confidence: 99%

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Dasabuvir Suppresses Esophageal Squamous Cell Carcinoma Growth As a Novel ROCK1 Inhibitor

Liu¹,

Jiang²,

Zhou³

et al. 2021

Preprint

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Background: Esophageal squamous cell carcinoma (ESCC) is a high recurrence rate of upper-digestive cancer with a low 5-year survival rate. Therefore, there is an urgent need for effective chemopreventive drugs that can extend the survival rate of patients. Through screening of FDA-approved drugs, dasabuvir was found to suppress ESCC proliferation. Methods: Cell number count assay was used to screen for drugs with inhibitory effect on ESCC cells and detect the inhibitory effect of dasabuvir on proliferation of ESCC cells KYSE150 and KYE450. Phosphoproteomics and proteomics were used to investigate the mechanism of dasabuvir inhibiting ESCC. In vitro kinase assay was used to verify the inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) activation by ROCK1 by dasabuvir. The PDX model was used to test the inhibitory effect of dasabuvir on ESCC in vivo.Results: In this study, we found that dasabuvir is a novel inhibitor of Rho-associated protein kinase 1 (ROCK1). Dasabuvir inhibited the growth of the KYSE150 and KYSE450 ESCC cell lines in a time and dose-dependent manner and arrested cell cycle at the G0/G1 phase. The antitumor activity was validated in vivo using a patient-derived xenograft tumor model in mice. Dasabuvir inhibited the activation of ERK1/2 by ROCK1 and downregulated cyclin-dependent kinase 4 (CDK4) and cyclin D1 expression. Conclusions: These results provide the first evidence that dasabuvir serves as a ROCK1 inhibitor, suppresses ESCC growth in vivo and in vitro, and arrests the cell cycle through the ROCK1/ERK signaling pathway.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Dasabuvir Suppresses Esophageal Squamous Cell Carcinoma Growth As a Novel ROCK1 Inhibitor

Liu¹,

Jiang²,

Zhou³

et al. 2021

Preprint

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“…Accumulating evidence supports the concept that ROCK plays vital roles in tumor development and progression through regulating many key cellular functions associated with malignancy, including tumorigenicity, tumor growth, metastasis, angiogenesis, tumor cell apoptosis/survival and chemoresistance. Since ROCK has emerged as a promising target for the development of novel anti-cancer drugs, the prospect of applying ROCK inhibition to delay and block tumorigenicity, tumor growth, tumor cell invasion and metastasis has been extensively evaluated (de Sousa et al 2020 ; Shahbazi et al 2020 ; Wei et al 2016 ). Although ROCK activation is generally considered to be oncogenic, some studies show ROCK functions as a negative regulator in cancer progression.…”

Section: Rocks Play Critical Roles In Stem Cell Renewal and Differentiationmentioning

confidence: 99%

“…Another potential explanation for contradictory contributions of ROCK signaling to cancer progression is relating to the pro-survival and proliferative effects of ROCK inhibition on cancer stem cells, dormant cells, and circulating tumor cells which are responsible for cancer cell dissemination and metastasis after ROCK inhibition (de Sousa et al 2020 ; Wei et al 2016 ). Cancer stem cells, also named tumor-initiating cells, represent a small subpopulation of cancer cells with self-renewable and multi or pluripotent abilities.…”

Section: Rocks Play Critical Roles In Stem Cell Renewal and Differentiationmentioning

confidence: 99%

“…Conditional reprogramming allows for the enrichment of cancer cells from urine (for bladder cancer), blood (for prostate cancer), pleural effusion (for non-small cell lung carcinoma), and from small biopsies and cryopreserved specimens of solid tumor tissues. This helps various biological assays including chemosensitivity testing for rapid screening of candidate drugs and developing individualized treatment plans (de Sousa et al 2020 ; Liu et al 2020 ; Palechor-Ceron et al 2019 ; Wu et al 2020 ). For example, conditional reprogramming helped to identify therapeutic strategies for a patient with recurrent respiratory papillomatosis with chemoresistant and progressive disease (Yuan et al 2012 ), perform personalized drug sensitivity screening for tongue squamous cell carcinoma using patient-derived matched normal and tumor models (Palechor-Ceron et al 2019 ) and for bladder cancer (Kettunen et al 2019 ), and to identify novel effective drug combination therapeutic strategies for prostate cancer (Vondalova Blanarova et al 2017 ) and non-small cell lung cancer (Crystal et al 2014 ).…”

Section: Rocks Play Critical Roles In Stem Cell Renewal and Differentiationmentioning

confidence: 99%

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Rho Kinases in Embryonic Development and Stem Cell Research

Shi

Wei

2022

Arch. Immunol. Ther. Exp.

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The Rho-associated coiled-coil containing kinases (ROCKs or Rho kinases) belong to the AGC (PKA/PKG/PKC) family of serine/threonine kinases and are major downstream effectors of small GTPase RhoA, a key regulator of actin-cytoskeleton reorganization. The ROCK family contains two members, ROCK1 and ROCK2, which share 65% overall identity and 92% identity in kinase domain. ROCK1 and ROCK2 were assumed to be functionally redundant, based largely on their major common activators, their high degree kinase domain homology, and study results from overexpression with kinase constructs or chemical inhibitors. ROCK signaling research has expanded to all areas of biology and medicine since its discovery in 1996. The rapid advance is befitting ROCK’s versatile functions in modulating various cell behavior, such as contraction, adhesion, migration, proliferation, polarity, cytokinesis, and differentiation. The rapid advance is noticeably driven by an extensive linking with clinical medicine, including cardiovascular abnormalities, aberrant immune responsive, and cancer development and metastasis. The rapid advance during the past decade is further powered by novel biotechnologies including CRISPR-Cas and single cell omics. Current consensus, derived mainly from gene targeting and RNA interference approaches, is that the two ROCK isoforms have overlapping and distinct cellular, physiological and pathophysiology roles. In this review, we present an overview of the milestone discoveries in ROCK research. We then focus on the current understanding of ROCK signaling in embryonic development, current research status using knockout and knockin mouse models, and stem cell research.

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Neferine, a novel ROCK1-targeting inhibitor, blocks EMT process and induces apoptosis in non-small cell lung cancer

Wan

et al. 2022

J Cancer Res Clin Oncol

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The compounds derived from Traditional Chinese Medicines have shown various pharmacological activities with unique advantages, especially in the aspect of anti-tumor. Neferine (Nef), a natural compound, extracted from green seed embryos of Lotus (Nelumbo nucifera Gaertn) also exerts antitumor effects on cancers. In this study, the effects and mechanisms of Nef on epithelial-to-mesenchymal transition (EMT) process in non-small cell lung cancer (NSCLC) were evaluated. The results showed that Nef had the antitumor effects in vivo and in vitro. Nef signi cantly suppressed cell viability and induced apoptosis in NSCLC cells, with elevated reactive oxygen species and reduced BCL-2 /BAX ratio. Nef was also demonstrated to inhibit the invasion, metastasis and EMT process of NSCLC cells, and attenuate EMT-related changes of E-cadherin, N-cadherin and Vimentin at both transcriptional and translational levels. Moreover, we concluded that the inhibitory effects of Nef on EMT was achieved by targeting Rhoassociated protein kinase 1 (ROCK1), a protein mediating the process of EMT in various cancers. These results showed that Nef had a signi cant antitumor effect on NSCLC cells by inducing apoptosis and blocking EMT, providing the therapeutical prospect on NSCLC treatment.

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Should we keep rocking? Portraits from targeting Rho kinases in cancer

Cited by 22 publications

References 249 publications

Dasabuvir Suppresses Esophageal Squamous Cell Carcinoma Growth As a Novel ROCK1 Inhibitor

Dasabuvir Suppresses Esophageal Squamous Cell Carcinoma Growth As a Novel ROCK1 Inhibitor

Rho Kinases in Embryonic Development and Stem Cell Research

Neferine, a novel ROCK1-targeting inhibitor, blocks EMT process and induces apoptosis in non-small cell lung cancer

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