LIM kinases: cofilin and beyond

Prunier, Chloé; Prudent, Renaud; Kapur, Reuben; Sadoul, Karin; Lafanechère, Laurence

doi:10.18632/oncotarget.16978

Cited by 77 publications

(69 citation statements)

References 90 publications

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“…One example of a Ca 2+ regulated kinase involved in cell movement is LIM domain kinase 1 (LIMK1) (16). LIMK1 regulates the organization of the actin cytoskeleton via phosphorylation of its downstream effector cofilin (27). Cancer cells rely on increased levels of LIMK1 to be able to invade the tissue that surrounds the tumor (28) and inhibition of LIMK1 reduces their invasiveness (29, 30).…”

mentioning

confidence: 99%

Neuronal calcium sensor 1 (NCS1) promotes motility and metastatic spread of breast cancer cells in vitro and in vivo

et al. 2018

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Increased levels of the calcium‐binding protein neuronal calcium sensor 1 (NCS1) predict an unfavorable patient outcome in several aggressive cancers, including breast and liver tumors. Previous studies suggest that NCS1 overexpression facilitates metastatic spread of these cancers. To investigate this hypothesis, we explored the effects of NCS1 overexpression on cell proliferation, survival, and migration patterns in vitro in 2‐ and 3‐dimensional (2/3‐D). Furthermore, we translated our results into an in vivo mouse xenograft model. Cell‐based proliferation assays were used to demonstrate the effects of overexpression of NCS1 on growth rates. In vitro colony formation and wound healing experiments were performed and 3‐D migration dynamics were studied using collagen gels. Nude mice were injected with breast cancer cells to monitor NCS1‐dependent metastasis formation over time. We observed that increased NCS1 levels do not change cellular growth rates, but do significantly increase 2‐ and 3‐D migration dynamics in vitro. Likewise, NCS1‐overexpressing cells have an increased capacity to form distant metastases and demonstrate better survival and less necrosis in vivo. We found that NCS1 preferentially localizes to the leading edge of cells and overexpression increases the motility of cancer cells. Furthermore, this phenotype is correlated with an increased number of metastases in a xenograft model. These results lay the foundation for exploring the relevance of an NCS1‐mediated pathway as a metastatic biomarker and as a target for pharmacologic interventions.—Apasu, J. E., Schuette, D., LaRanger, R., Steinle, J. A., Nguyen, L. D., Grosshans, H. K., Zhang, M., Cai, W. L., Yan, Q., Robert, M. E., Mak, M., Ehrlich, B. E. Neuronal calcium sensor 1 (NCS1) promotes motility and metastatic spread of breast cancer cells in vitro and in vivo. FASEB J. 33, 4802–4813 (2019). http://www.fasebj.org

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confidence: 99%

Neuronal calcium sensor 1 (NCS1) promotes motility and metastatic spread of breast cancer cells in vitro and in vivo

et al. 2018

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“…The degree of Rac signaling plays a crucial role in the balance between differentiation and proliferation; cellular Rac1 is indispensable for differentiation (35), and RhoA/ROCK signaling plays an important role in differentiation induction (36). The activation of Rho and Rac1 can phosphorylate the kinase ROCK and activate LIMK1, as Rac can activate LIMK1, which induces cofilin 1 phosphorylation at Ser3 and thus regulates the actin cytoskeleton; this process indicates the formation of the Rac1-ROCK1/LIMK1-cofilin signaling pathway by regulating tumor cell migration and invasion (37,38). The inhibition of the ROCK/PTEN pathway and cofilin-1 expression is involved in the induction of cancer cell apoptosis (39).…”

Section: Groupmentioning

confidence: 99%

Diallyl disulfide induces downregulation and inactivation of cofilin�1 differentiation via the Rac1/ROCK1/LIMK1 pathway in leukemia cells

Ling

Lei

et al. 2020

Int J Oncol

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Cofilin is associated with cell differentiation; however, to the best of our knowledge, no data have indicated an association between the cofilin 1 pathway and leukemia cell differentiation. The present study investigated the involvement of the cofilin 1 signaling pathway in diallyl disulfide (DADS)-induced differentiation and the inhibitory effects on the proliferation, migration, and invasion of human leukemia HL-60 cells. First, it was identified that 8 µM DADS suppressed cell proliferation, migration and invasion, and induced differentiation based on the reduced nitroblue tetrazolium ability and increased CD11b and CD33 expression. DADS significantly downregulated the expression of cofilin 1 and phosphorylated cofilin 1 in HL-60 leukemia cells. Second, it was verified that silencing cofilin 1 markedly promoted 8 µM DADS-induced differentiation and the inhibitory effect on cell proliferation and invasion. Overexpression of cofilin 1 obviously suppressed 8 µM DADS-induced differentiation and the inhibitory effect on cell proliferation and invasion. Third, the present study examined the mechanisms by which 8 µM DADS decreases cofilin 1 expression and activation. The results revealed that 8 µM DADS inhibited the mRNA and protein expression of Rac1, Rho-associated protein kinase 1 (ROCK1) and LIM domain kinase 1 (LIMK1) as well as the phosphorylation of LIMK1 in HL-60 cells, while 8 µM DADS enhanced the effects of the Rac1-ROCK1-LIMK1 pathway in cells overexpressing cofilin 1 compared with that in control HL-60 cells. These results suggest that the anticancer function of DADS on HL-60 leukemia cells is regulated by the Rac1-ROCK1-LIMK1-cofilin 1 pathway, indicating that DADS could be a promising anti-leukemia therapeutic compound.

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“…For example, the high-confidence hit LIMK1 is downstream of Rac (human Rac1 and Rac2), which promotes membrane protrusions in migrating cells 49,50 . Similarly, Cdc42 stimulates actinrich protrusions and can polarize migrating cells through direct binding to Par-6 (human PARD6B/PARD6G), one of the strongest hits from the border cell screen 51,52,53 , and has a welldescribed role in GBM invasion 54 .…”

Section: Group 1 Genes) and Lower Confidence Genes (Only One Rnai Linmentioning

confidence: 99%

Identifying conserved molecular targets required for cell migration of glioblastoma cancer stem cells

Volovetz

Berezovsky

Alban

et al. 2019

Preprint

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Glioblastoma (GBM) is the most prevalent primary malignant brain tumor and is associated with extensive tumor cell infiltration into the adjacent brain parenchyma. However, there are limited targeted therapies that address this disease hallmark. While the invasive capacity of self-renewing cancer stem cells (CSCs) and their non-CSC progeny has been investigated, the mode(s) of migration used by CSCs during invasion is currently unknown. Here we used time-lapse microscopy to evaluate the migratory behavior of CSCs, with a focus on identifying key regulators of migration. A head-to-head migration assay demonstrated that CSCs are more invasive than non-CSCs. Time-lapse live cell imaging further revealed that GBM patient-derived CSC models either migrate in a collective manner or in a single cell fashion. To uncover conserved molecular regulators responsible for collective cell invasion, we utilized the genetically tractable Drosophila border cell collective migration model. Candidates for functional studies were generated using results from a targeted Drosophila genetic screen followed by gene expression analysis of the human homologs in GBM tumors and associated GBM patient prognosis. This strategy identified the highly conserved small GTPase, Rap1a, as a potential regulator of cell invasion. Alteration of Rap1a activity impaired the forward progress of Drosophila border cells during development.Rap1a expression was elevated in GBM and associated with higher tumor grade. Functionally, the levels of activated Rap1a impacted CSC migration speed out of spheres onto extracellular matrix. The data presented here demonstrate that CSCs are more invasive than non-CSCs, are capable of both collective and single cell migration, and express conserved genes that are required for migration and invasion. Using this integrated approach, we identified a new role for Rap1a in the migration of GBM CSCs. RAP1A

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LIM kinases: cofilin and beyond

Cited by 77 publications

References 90 publications

Neuronal calcium sensor 1 (NCS1) promotes motility and metastatic spread of breast cancer cells in vitro and in vivo

Neuronal calcium sensor 1 (NCS1) promotes motility and metastatic spread of breast cancer cells in vitro and in vivo

Diallyl disulfide induces downregulation and inactivation of cofilin�1 differentiation via the Rac1/ROCK1/LIMK1 pathway in leukemia cells

Identifying conserved molecular targets required for cell migration of glioblastoma cancer stem cells

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