Suppression of KRas-mutant cancer through the combined inhibition of KRAS with PLK1 and ROCK

Wang, Jieqiong; Hu, Kewen; Guo, Jiawei; Cheng, Feixiong; Lv, Jing; Jiang, Wenhao; Lü, Weiqiang; Liu, Jinsong; Pang, Xiufeng; Liu, Mingyao

doi:10.1038/ncomms11363

Cited by 82 publications

(68 citation statements)

References 56 publications

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“…Fasudil is a potent Rho-associated protein kinase (ROCK) inhibitor [8,9,10,11,12,13] and vasodilator and has been used for the treatment of cerebral vasospasm [9] and many other diseases, such as cancer [14,15], allergy [16] and inflammation [17,18]. The systematic administration of Fasudil was reported protecting mice from experimental autoimmune encephalomyelitis (EAE) and shifting macrophages from M1 to M2 [19].…”

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: Macrophage-targeting Fasudil treatment protects liver from the ischemia/reperfusion injury by promoting M2 macrophage polarization

et al. 2018

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Macrophages play essential roles in the generation and resolution of inflammation. Ischemia-reperfusion injury (IRI) triggers a systemic inflammatory response and leads to cellular injury and organ failure.During surgical procedures of the liver, such as hepatic resection and liver transplantation, IRI leads to the dysfunction of the liver. Rho-associated protein kinase (ROCK) inhibitors were reported protecting the liver from IRI. However, the systematic administration of ROCK inhibitors causes severe hypotension.Here, using Fasudil carried liposomes, we specifically inhibited the ROCK-II expression in Kupffer cells and blood monocytes. Through this macrophage/monocyte specific treatment of Fasudil, we successfully protected the liver from IRI by shifting Kupffer cells/monocytes from M1/classical to M2/patrolling phenotype in the liver and peripheral blood. Our finding provides novel insights into the macrophage/monocyte-specific drug delivery and the treatment of liver IRI.

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Section: Introductionmentioning

confidence: 99%

WITHDRAWN: Macrophage-targeting Fasudil treatment protects liver from the ischemia/reperfusion injury by promoting M2 macrophage polarization

et al. 2018

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“…The effect of drugs on cell viability was measured using CellTiter 96 ® AQueous One Solution from Promega (Madison, WI) as previously described [45]. The IC 50 values were calculated by Prism 5 (GraphPad Software, La Jolla, CA).…”

Section: Methodsmentioning

confidence: 99%

Inhibiting cytoplasmic accumulation of HuR synergizes genotoxic agents in urothelial carcinoma of the bladder

Guo

Chang

et al. 2016

Oncotarget

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HuR, an RNA-binding protein, post-transcriptionally regulates nearly 4% of encoding proteins implicated in cell survival. Here we show that HuR is required for the efficacy of chemotherapies in urothelial carcinoma of the bladder. We identify pyrvinium pamoate, an FDA-approved anthelminthic drug, as a novel HuR inhibitor that dose-dependently inhibited cytoplasmic accumulation of HuR. Combining pyrvinium pamoate with chemotherapeutic agents (e.g. cisplatin, doxorubicin, vincristine and oxaliplatin) not only led to enhanced cytotoxicity in bladder cancer cells but also synergistically suppressed the growth of patient-derived bladder tumor xenografts in mice (P < 0.001). Mechanistically, pyrvinium pamoate promoted nuclear import of HuR by activating the AMP-activated kinase/importin α1 cascade and blocked HuR nucleo-cytoplasmic translocation by inhibiting the checkpoint kinase1/cyclin-dependent kinase 1 pathway. Notably, pyrvinium pamoate-additive treatment increased DNA double-strand breaks as indicated by elevated γH2AX expression, suggesting an involvement of DNA damage response. We further found that pyrvinium pamoate dramatically downregulated several key DNA repair genes in genotoxically-stressed cells, including DNA ligase IV and BRCA2, leading to unbearable genomic instability and cell death. Collectively, our findings are the first to characterize a clinical HuR inhibitor and provide a novel therapeutically tractable strategy by targeting cytoplasmic translocation of HuR for treatment of urothelial carcinoma of the bladder.

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“…In fact, Plk1 inhibition may be particularly effective in Ras-(Refs. 63,73 ) or Her2-(Ref. 74 ) induced tumors indicating that, independently of a possible tumor suppressor role of overexpressed Plk1, efficient kinase inhibition of this protein may impair tumor cell proliferation and survival.…”

Section: Discussionmentioning

confidence: 99%

Plk1 overexpression suppresses tumor development by inducing chromosomal instability

Cárcer

Venkateswaran

Salgueiro

et al. 2018

Preprint

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Polo-like kinase 1 (Plk1) is a protein kinase currently considered as an attractive cancer target due to its critical role in the cell division cycle. Plk1 is overexpressed in a wide spectrum of human tumors, being frequently considered as an oncogene. However, its contribution to tumor development is unclear. Using a new inducible knock-in mouse model we report here that Plk1 overexpression does not favor cell proliferation but rather results in abnormal chromosome segregation and cytokinesis, leading to the formation of polyploid cells with reduced proliferative potential. Mechanistically, these cytokinesis defects correlate with defective loading of Cep55 and ESCRT complexes to the abscission bridge during cytokinesis in a Plk1 kinase-dependent manner. In vivo, elevated levels of Plk1 markedly prevent the development of mammary gland tumors induced either by Kras G12D or Her2, in the presence of increased rates of chromosome instability. In patients, higher Plk1 expression levels are associated with significantly increased overall survival in breast cancer subtypes. These data suggest that, despite the therapeutic benefits of inhibiting Plk1 due to its essential role in tumor cell cycles, Plk1 overexpression has tumor suppressive properties by perturbing mitotic progression and cytokinesis.

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Suppression of KRas-mutant cancer through the combined inhibition of KRAS with PLK1 and ROCK

Cited by 82 publications

References 56 publications

WITHDRAWN: Macrophage-targeting Fasudil treatment protects liver from the ischemia/reperfusion injury by promoting M2 macrophage polarization

WITHDRAWN: Macrophage-targeting Fasudil treatment protects liver from the ischemia/reperfusion injury by promoting M2 macrophage polarization

Inhibiting cytoplasmic accumulation of HuR synergizes genotoxic agents in urothelial carcinoma of the bladder

Plk1 overexpression suppresses tumor development by inducing chromosomal instability

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