Targeting LIM kinases in taxane resistant tumors

Prunier, Chloé; Kapur, Reuben; Lafanechère, Laurence

doi:10.18632/oncotarget.10816

Cited by 8 publications

(7 citation statements)

References 7 publications

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“…A possible similar residual cofilin phosphorylation could also explain why LIMK inhibition did not reduce spontaneous metastasis in animal tumor models [16, 51].…”

Section: Discussionmentioning

confidence: 99%

“…Conversely, the described antitumor effect of LIMK inhibition could involve other subtrates than cofilin. It has been shown that the microtubule cytoskeleton is also impacted by LIMK inhibition [9, 10, 16], by yet unknown mechanisms [3]. There are also evidences that LIMK may bind to and regulate other proteins [15, 52–54], so that other, known or yet unknown substrates may mediate antitumor effects of LIMK inhibition, independently of cofilin.…”

Section: Discussionmentioning

confidence: 99%

“…Western blotting with phospho-S3 cofilin-specific antibodies, show in most cases a strong decrease of S3 phosphorylation [9–14]. Recent findings indicate that pharmacological inhibition of LIMK has a strong effect on the growth and invasive behavior of breast cancer cells in 3D cell models [15] and in animal tumor models [16]. Such a treatment was well-tolerated and showed efficacy even on taxane resistant tumors [16].…”

Section: Introductionmentioning

confidence: 99%

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A quantitative proteomic analysis of cofilin phosphorylation in myeloid cells and its modulation using the LIM kinase inhibitor Pyr1

Prudent¹,

Demoncheaux²,

Diemer

et al. 2018

PLoS ONE

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LIM kinases are located at a strategic crossroad, downstream of several signaling pathways and upstream of effectors such as microtubules and the actin cytoskeleton. Cofilin is the only LIM kinases substrate that is well described to date, and its phosphorylation on serine 3 by LIM kinases controls cofilin actin-severing activity. Consequently, LIM kinases inhibition leads to actin cytoskeleton disorganization and blockade of cell motility, which makes this strategy attractive in anticancer treatments. LIMK has also been reported to be involved in pathways that are deregulated in hematologic malignancies, with little information regarding cofilin phosphorylation status. We have used proteomic approaches to investigate quantitatively and in detail the phosphorylation status of cofilin in myeloid tumor cell lines of murine and human origin. Our results show that under standard conditions, only a small fraction (10 to 30% depending on the cell line) of cofilin is phosphorylated (including serine 3 phosphorylation). In addition, after a pharmacological inhibition of LIM kinases, a residual cofilin phosphorylation is observed on serine 3. Interestingly, this 2D gel based proteomic study identified new phosphorylation sites on cofilin, such as threonine 63, tyrosine 82 and serine 108.

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“…A possible similar residual cofilin phosphorylation could also explain why LIMK inhibition did not reduce spontaneous metastasis in animal tumor models [16, 51].…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A quantitative proteomic analysis of cofilin phosphorylation in myeloid cells and its modulation using the LIM kinase inhibitor Pyr1

Prudent¹,

Demoncheaux²,

Diemer

et al. 2018

PLoS ONE

Self Cite

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“…MCF10A cell motility inhibition was also observed in vitro with time lapse video microscopy. The effects of Pyr1 were also studied on these different breast cancer cell lines: TS-A-pGL3 and MDA-MB-231 [58]. In these cells, it inhibited cofilin phosphorylation, and actin dynamics were strongly diminished, with reduced filopodiumlike protrusions in number and size.…”

Section: Pyr1 Derivativesmentioning

confidence: 99%

“…Furthermore, Pyr1 did not affect the number of lung metastases; however, their size was reduced. When MDA-MB-231 cells were directly injected into the bloodstream of Pyr1-treated mice, the number of metastases was not reduced, although a significant decrease in the global metastatic load was observed, and this effect lasted several days after the end of the Pyr1-treatment [58]. For Schizophrenia, MAP6 KO mice were used.…”

Section: Pyr1 Derivativesmentioning

confidence: 99%

LIM Kinases, Promising but Reluctant Therapeutic Targets: Chemistry and Preclinical Validation In Vivo

Berabez

Routier

Bénédetti

et al. 2022

Cells

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LIM Kinases are important actors in the regulation of cytoskeleton dynamics by controlling microtubule and actin filament turnover. The signaling pathways involving LIM kinases for actin filament remodeling are well established. They are downstream effectors of small G proteins of the Rho-GTPases family and have become promising targets for the treatment of several major diseases because of their position at the lower end of these signaling cascades. Cofilin, which depolymerizes actin filaments, is the best-known substrate of these enzymes. The phosphorylation of cofilin to its inactive form by LIM kinases avoids actin filament depolymerization. The balance between phosphorylated and non-phosphorylated cofilin is thought to play an important role in tumor cell invasion and metastasis. Since 2006, many small molecules have been developed for LIMK inhibition, and in this review article, we will discuss the structure–activity relationships of the few inhibitor families that have been tested in vivo on different pathological models.

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Diallyl disulfide downregulating RhoGDI2 induces differentiation and inhibit invasion via the Rac1/Pak1/LIMK1 pathway in human leukemia HL‐60 cells

Tan

Jiang

Guangqun

et al. 2023

Environmental Toxicology

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Leukemia is a type of disease in which hematopoietic stem cells proliferate clonally at the genetic level. We discovered previously by high-resolution mass spectrometry that diallyl disulfide (DADS), which is one of the effective ingredients of garlic, reduces the performance of RhoGDI2 from APL HL-60 cells. Although RhoGDI2 is oversubscribed in several cancer categories, the effect of RhoGDI2 in HL-60 cells has remained unexplained. We aimed to investigate the influence of RhoGDI2 on DADSinduced differentiation of HL-60 cells to elucidate the association among the effect of inhibition or over-expression of RhoGDI2 with HL-60 cell polarization, migration and invasion, which is important for establishing a novel generation of inducers to elicit leukemia cell polarization. Co-transfection with RhoGDI2-targeted miRNAs apparently decreases the malignant biological behavior of cells and upregulates cytopenias in DADS-treated HL-60 cell lines, which increases CD11b and decreases CD33 and mRNA levels of Rac1, PAK1 and LIMK1. Meanwhile, we generated HL-60 cell lines with high-expressing RhoGDI2. The proliferation, migration and invasion capacity of such cells were significantly increased by the treated with DADS, while the reduction capacity of the cells was decreased. There was a reduction in CD11b and an increase in CD33 production, as well as an increase in the mRNA levels of Rac1, PAK1 and LIMK1. It also confirmed that inhibition of RhoGDI2 attenuates the EMT cascade via the Rac1/Pak1/LIMK1 pathway, thereby inhibiting the malignant biological behavior of HL-60 cells. Thus, we considered that inhibition of RhoGDI2 expression might be a new therapeutic direction for the treatment of human promyelocytic leukemia. The anti-cancer property of DADS against HL-60 leukemia cells might be regulated by RhoGDI2 through the Rac1-Pak1-LIMK1 pathway, which provides new evidence for DADS as a clinical anti-cancer medicine.

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Targeting LIM kinases in taxane resistant tumors

Cited by 8 publications

References 7 publications

A quantitative proteomic analysis of cofilin phosphorylation in myeloid cells and its modulation using the LIM kinase inhibitor Pyr1

A quantitative proteomic analysis of cofilin phosphorylation in myeloid cells and its modulation using the LIM kinase inhibitor Pyr1

LIM Kinases, Promising but Reluctant Therapeutic Targets: Chemistry and Preclinical Validation In Vivo

Diallyl disulfide downregulating RhoGDI2 induces differentiation and inhibit invasion via the Rac1/Pak1/LIMK1 pathway in human leukemia HL‐60 cells

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