Adducins inhibit lung cancer cell migration through mechanisms involving regulation of cell-matrix adhesion and cadherin-11 expression

Lechuga, Susana; Amin, Parth H.; Wolen, Aaron R.; Ivanov, Andrei I.

doi:10.1016/j.bbamcr.2018.10.001

Cited by 30 publications

(36 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cells were infected with Toxoplasma at an MOI of 3 for 18 h and then trypsinized and counted using a hemocytometer; 2 ϫ 10 4 cells were resuspended in serum-free medium and applied to the top of a membrane coated with collagen I (rat tail) (Gibco; A1048301). Transmigration assays were carried out using a Corning Transwell Costar apparatus (6.5-mm diameter and 8-m pore size) as described previously (32). After 18 h for MEFs and 6 h for DCs and macrophages, the medium was removed, and the cells were fixed with 2.5% paraformaldehyde for 20 min.…”

Section: Methodsmentioning

confidence: 99%

Toxoplasma gondii Co-opts the Unfolded Protein Response To Enhance Migration and Dissemination of Infected Host Cells

Augusto

Martynowicz

Amin

et al. 2020

mBio

Self Cite

View full text Add to dashboard Cite

ABSTRACT Toxoplasma gondii is an intracellular parasite that reconfigures its host cell to promote pathogenesis. One consequence of Toxoplasma parasitism is increased migratory activity of host cells, which facilitates dissemination. Here, we show that Toxoplasma triggers the unfolded protein response (UPR) in host cells through calcium release from the endoplasmic reticulum (ER). We further identify a novel role for the host ER stress sensor protein IRE1 in Toxoplasma pathogenesis. Upon infection, Toxoplasma activates IRE1, engaging its noncanonical role in actin remodeling through the binding of filamin A. By inducing cytoskeletal remodeling via IRE1 oligomerization in host cells, Toxoplasma enhances host cell migration in vitro and dissemination of the parasite to host organs in vivo. Our study has identified novel mechanisms used by Toxoplasma to induce dissemination of infected cells, providing new insights into strategies for treatment of toxoplasmosis. IMPORTANCE Cells that are infected with the parasite Toxoplasma gondii exhibit heightened migratory activity, which facilitates dissemination of the infection throughout the body. In this report, we identify a new mechanism used by Toxoplasma to hijack its host cell and increase its mobility. We further show that the ability of Toxoplasma to increase host cell migration involves not the enzymatic activity of IRE1 but rather IRE1 engagement with actin cytoskeletal remodeling. Depletion of IRE1 from infected host cells reduces their migration in vitro and significantly hinders dissemination of Toxoplasma in vivo. Our findings reveal a new mechanism underlying host-pathogen interactions, demonstrating how host cells are co-opted to spread a persistent infection around the body.

show abstract

Section: Methodsmentioning

confidence: 99%

Toxoplasma gondii Co-opts the Unfolded Protein Response To Enhance Migration and Dissemination of Infected Host Cells

Augusto

Martynowicz

Amin

et al. 2020

mBio

Self Cite

View full text Add to dashboard Cite

show abstract

“…Cells were infected with Toxoplasma MOI 3 for 18 h and then trypsinized and counted using a hemocytometer; 2×10 4 cells were resuspended in serum-free medium and applied to the top of a membrane coated with collagen I (rat-tail) (Gibco- A1048301). Transmigration assays were carried out using a Corning Transwell Costar apparatus (6.5 mm diameter and 8 µm pore size) as described [32]. After 18 h for MEF and 6 h for DCs and macrophages, the medium was removed, and the cells were fixed with 2.5% paraformaldehyde for 20 min.…”

Section: Methodsmentioning

confidence: 99%

Toxoplasma gondiico-opts the unfolded protein response to enhance migration and dissemination of infected host cells

Augusto

Martynowicz

Amin

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

26Toxoplasma gondii is an intracellular parasite that reconfigures its host cell to promote 27 pathogenesis. One consequence of Toxoplasma parasitism is increased migratory activity of host 28 cells, which facilitates dissemination. Here we show that Toxoplasma triggers the unfolded 29 protein response (UPR) in host cells through calcium release from the endoplasmic reticulum 30 (ER). We further found that host IRE1, an ER stress sensor protein activated during Toxoplasma 31 infection, also plays a noncanonical role in actin remodeling by binding filamin A in infected 32 cells. By inducing cytoskeletal remodeling via IRE1 oligomerization in host cells, Toxoplasma 33 enhances host cell migration in vitro and dissemination of the parasite to host organs in vivo. Our 34 study identifies novel mechanisms used by Toxoplasma to induce dissemination of infected cells, 35 providing new insights into strategies for treatment of toxoplasmosis. 36 37 interactions 39 3 Importance 40Cells that are infected with the parasite Toxoplasma gondii exhibit heightened migratory 41 activity, which facilitates dissemination of the infection throughout the body. In this study, we 42 identify a new mechanism used by Toxoplasma to hijack its host cell and increase its mobility. 43 We further show that the ability of Toxoplasma to increase host cell migration does not involve 44 the enzymatic activity of IRE1, but rather IRE1 engagement with actin cytoskeletal remodeling. 45 Depletion of IRE1 from infected host cells reduces their migration in vitro and significantly 46 hinders dissemination of Toxoplasma in vivo. Our findings reveal a new mechanism underlying 47 host-pathogen interactions, demonstrating how host cells are co-opted to spread a persistent 48 infection around the body. 49 50 93 leading to IRE1 oligomerization, association with filamin A, and enhanced cell migration.94 Importantly, the IRE1-associated migration is a crucial determinant for successful dissemination 95 of toxoplasmosis in a mouse model of infection. 96 6 Results 97 Induction of the UPR in Toxoplasma-infected host cells 98 It is currently unclear why intracellular tachyzoites recruit host ER to the parasite PV. To 99 address whether Toxoplasma perturbs host ER homeostasis, we infected mouse embryonic 100 fibroblast (MEF) cells with RH strain parasites and measured three primary markers of the host 101 UPR over a 36-hour time course. Within 12 h of infection, Toxoplasma increased activation of 102 PERK as measured by its self-phosphorylation (PERK-P), induced expression of ATF6 and 103 formation of its cleavage product ATF6-N, and increased levels of the IRE1-derived spliced 104 variant of XBP1 (XBP1s) ( Fig. 1A). It is noteworthy that whereas expression of ATF6-N and 105 XBP1s were transient, with increased amounts of the proteins appearing between 12 to 20 h post-106 infection (hpi), PERK-P increased throughout the 36 h of infection (Fig. 1A). These results 107 indicate that Toxoplasma infection causes ER stress that activates each of the sensory prote...

show abstract

“…Cell-matrix adhesion assay was performed as previously described [41]. Briefly, control, anillin-depleted, and anillinoverexpressing cells were dissociated by the TrypLE Express reagent, counted with a hemocytometer, and resuspended in the complete medium.…”

Section: Extracellular Matrix Adhesion Assaymentioning

confidence: 99%

Anillin regulates breast cancer cell migration, growth, and metastasis by non-canonical mechanisms involving control of cell stemness and differentiation

et al. 2020

Self Cite

View full text Add to dashboard Cite

Background: Breast cancer metastasis is driven by a profound remodeling of the cytoskeleton that enables efficient cell migration and invasion. Anillin is a unique scaffolding protein regulating major cytoskeletal structures, such as actin filaments, microtubules, and septin polymers. It is markedly overexpressed in breast cancer, and high anillin expression is associated with poor prognosis. The aim of this study was to investigate the role of anillin in breast cancer cell migration, growth, and metastasis. Methods: CRISPR/Cas9 technology was used to deplete anillin in highly metastatic MDA-MB-231 and BT549 cells and to overexpress it in poorly invasive MCF10AneoT cells. The effects of anillin depletion and overexpression on breast cancer cell motility in vitro were examined by wound healing and Matrigel invasion assays. Assembly of the actin cytoskeleton and matrix adhesion were evaluated by immunofluorescence labeling and confocal microscopy. In vitro tumor development was monitored by soft agar growth assays, whereas cancer stem cells were examined using a mammosphere formation assay and flow cytometry. The effects of anillin knockout on tumor growth and metastasis in vivo were determined by injecting control and anillin-depleted breast cancer cells into NSG mice. Results: Loss-of-function and gain-of-function studies demonstrated that anillin is necessary and sufficient to accelerate migration, invasion, and anchorage-independent growth of breast cancer cells in vitro. Furthermore, loss of anillin markedly attenuated primary tumor growth and metastasis of breast cancer in vivo. In breast cancer cells, anillin was localized in the nucleus; however, knockout of this protein affected the cytoplasmic/cortical events, e.g., the organization of actin cytoskeleton and cell-matrix adhesions. Furthermore, we observed a global transcriptional reprogramming of anillin-depleted breast cancer cells that resulted in suppression of their stemness and induction of the mesenchymal to epithelial trans-differentiation. Such trans-differentiation was manifested by the upregulation of basal keratins along with the increased expression of E-cadherin and P-cadherin. Knockdown of E-cadherin restored the impaired migration and invasion of anillin-deficient breast cancer cells.

show abstract

Adducins inhibit lung cancer cell migration through mechanisms involving regulation of cell-matrix adhesion and cadherin-11 expression

Cited by 30 publications

References 74 publications

Toxoplasma gondii Co-opts the Unfolded Protein Response To Enhance Migration and Dissemination of Infected Host Cells

Toxoplasma gondii Co-opts the Unfolded Protein Response To Enhance Migration and Dissemination of Infected Host Cells

Toxoplasma gondiico-opts the unfolded protein response to enhance migration and dissemination of infected host cells

Anillin regulates breast cancer cell migration, growth, and metastasis by non-canonical mechanisms involving control of cell stemness and differentiation

Contact Info

Product

Resources

About