Suppression of phospho-p85α-GTP-Rac1 lipid raft interaction by bichalcone analog attenuates cancer cell invasion

The specialized cholesterol/sphingolipid-rich membrane domains termed lipid rafts are highly dynamic in the cancer cells, which rapidly assemble effector molecules to form a sorting platform essential for oncogenic signaling transduction in response to extra- or intracellular stimuli. Density-based membrane flotation, subcellular fractionation, cell surface biotinylation, and co-immunoprecipitation analyses of bichalcone analog ((E)-1-(4-Hydroxy-3-((4-(4-((E)-3-(pyridin-3-yl)acryloyl)phenyl)piperazin-1-yl)methyl)phenyl)-3-(pyridin-3-yl)prop-2-en-1-one (TSWU-BR4)-treated cancer cells showed dissociation between GRP78 and p85α conferring the recruitment of PTEN to lipid raft membranes associated with p85α. Ectopic expression of GRP78 could overcome induction of lipid raft membrane-associated p85α–unphosphorylated PTEN complex formation and suppression of GRP78−PI3K−Akt−GTP-Rac1-mediated and GRP78-regulated PERK−Nrf2 antioxidant pathway and cancer cell invasion by TSWU-BR4. Using specific inducer, inhibitor, or short hairpin RNA for ASM demonstrated that induction of the lipid raft membrane localization and activation of ASM by TSWU-BR4 is responsible for perturbing homeostasis of cholesterol and ceramide levels in the lipid raft and ER membranes, leading to alteration of GRP78 membrane trafficking and subsequently inducing p85α–unphosphorylated PTEN complex formation, causing disruption of GRP78−PI3K−Akt−GTP-Rac1-mediated signal and ER membrane-associated GRP78-regulated oxidative stress balance, thus inhibiting cancer cell invasion. The involvement of the enrichment of ceramide to lipid raft membranes in inhibition of NF-κB-mediated MMP-2 expression was confirmed through attenuation of NF-κB activation using C2-ceramide, NF-κB specific inhibitors, ectopic expression of NF-κB p65, MMP-2 promoter-driven luciferase, and NF-κB-dependent reporter genes. In conclusion, localization of ASM in the lipid raft membranes by TSWU-BR4 is a key event for initiating formation of ceramide-enriched lipid raft membrane platforms, which causes delocalization of GRP78 from the lipid raft and ER membranes to the cytosol and formation of p85α–unphosphorylated PTEN complexes to attenuate the GRP78-regulated oxidative stress balance and GRP78−p85α−Akt−GTP-Rac1−NF-κB−MMP-2-mediated cancer cell invasion.

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Faculty Opinions recommendation of α5β1 integrin recycling promotes Arp2/3-independent cancer cell invasion via the formin FHOD3.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725788040.793510040 ◽

2015 ◽

Author(s):

Kenneth Yamada ◽

Ryan Petrie

Keyword(s):

Cancer Cell ◽

Cell Invasion ◽

Cancer Cell Invasion ◽

Α5β1 Integrin

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Faculty Opinions recommendation of A mechanically active heterotypic E-cadherin/N-cadherin adhesion enables fibroblasts to drive cancer cell invasion.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727326037.793537869 ◽

2017 ◽

Author(s):

Eric Theveneau

Keyword(s):

Cancer Cell ◽

Cell Invasion ◽

Cancer Cell Invasion ◽

E Cadherin

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Faculty Opinions recommendation of A mechanically active heterotypic E-cadherin/N-cadherin adhesion enables fibroblasts to drive cancer cell invasion.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727326037.793533600 ◽

2017 ◽

Author(s):

Mirna Perez-Moreno

Keyword(s):

Cancer Cell ◽

Cell Invasion ◽

Cancer Cell Invasion ◽

E Cadherin

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When Neighbors Talk: Colon Cancer Cell Invasion and Tumor Microenvironment Myofibroblasts

Current Drug Targets ◽

10.2174/1389450117666161028142351 ◽

2017 ◽

Vol 18 (8) ◽

pp. 964-982 ◽

Cited By ~ 4

Author(s):

Jolien Bridelance ◽

Zuzanna Drebert ◽

Olivier De Wever ◽

Marc Bracke ◽

Ilse M. Beck

Keyword(s):

Colon Cancer ◽

Tumor Microenvironment ◽

Cancer Cell ◽

Cell Invasion ◽

Colon Cancer Cell ◽

Cancer Cell Invasion

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A Review on Phytopharmaceutical shaving Concomitant Experimental Anti-Diabetic and Anti-Cancer Effects as Potential Sources for Targeted Therapies Against Insulin Mediated Breast Cancer Cell Invasion and Migration

Current Cancer Therapy Reviews ◽

10.2174/1573394716999200831113335 ◽

2020 ◽

Vol 16 ◽

Author(s):

Vibhavana Singh ◽

Rakesh Reddy ◽

Antarip Sinha ◽

Venkatesh Marturi ◽

Shravani Sripathi Panditharadyula ◽

...

Keyword(s):

Breast Cancer ◽

Medicinal Plants ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Cell Invasion ◽

Breast Tumor ◽

Cancer Cell Invasion ◽

Invasion And Migration ◽

Anti Cancer ◽

And Migration

: Diabetes and breast cancer are pathophysiologically similar and clinically established diseases that co-exist with a wider complex similar molecular signalling and having similar set of risk factors. Insulin plays a pivotal role for invasion and migration of breast cancer cells. Several ethnopharmacological evidences light the concomitant anti-diabetic and anti-cancer activity of medicinal plant and phytochemicals against breast tumor of patients with diabetes. This present article reviewed the findings on medicinal plants and phytochemicals with concomitant anti-diabetic and anti-cancer effects reported in scientific literature to facilitate the development of dual-acting therapies against diabetes and breast cancer. The schematic tabular form of published literatures on medicinal plants (63 plants belongs to 45 families) concluded the dynamics of phytochemicals against diabetes and breast tumor that could be explored further for the discovery of therapies for controlling of breast cancer cell invasion and migration in patient with diabetes.

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EB1 Restricts Breast Cancer Cell Invadopodia Formation and Matrix Proteolysis via FAK

Cells ◽

10.3390/cells10020388 ◽

2021 ◽

Vol 10 (2) ◽

pp. 388

Author(s):

Brice Chanez ◽

Kevin Ostacolo ◽

Ali Badache ◽

Sylvie Thuault

Keyword(s):

Breast Cancer ◽

Cancer Cell ◽

Cell Invasion ◽

Focal Adhesions ◽

Matrix Degradation ◽

Cancer Cell Invasion ◽

Wild Type ◽

Spatial Regulation ◽

Invadopodia Formation

Regulation of microtubule dynamics by plus-end tracking proteins (+TIPs) plays an essential role in cancer cell migration. However, the role of +TIPs in cancer cell invasion has been poorly addressed. Invadopodia, actin-rich protrusions specialized in extracellular matrix degradation, are essential for cancer cell invasion and metastasis, the leading cause of death in breast cancer. We, therefore, investigated the role of the End Binding protein, EB1, a major hub of the +TIP network, in invadopodia functions. EB1 silencing increased matrix degradation by breast cancer cells. This was recapitulated by depletion of two additional +TIPs and EB1 partners, APC and ACF7, but not by the knockdown of other +TIPs, such as CLASP1/2 or CLIP170. The knockdown of Focal Adhesion Kinase (FAK) was previously proposed to similarly promote invadopodia formation as a consequence of a switch of the Src kinase from focal adhesions to invadopodia. Interestingly, EB1-, APC-, or ACF7-depleted cells had decreased expression/activation of FAK. Remarkably, overexpression of wild type FAK, but not of FAK mutated to prevent Src recruitment, prevented the increased degradative activity induced by EB1 depletion. Overall, we propose that EB1 restricts invadopodia formation through the control of FAK and, consequently, the spatial regulation of Src activity.

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CC Chemokine Ligand 7 Derived from Cancer-Stimulated Macrophages Promotes Ovarian Cancer Cell Invasion

Cancers ◽

10.3390/cancers13112745 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2745

Author(s):

Miran Jeong ◽

Yi-Yue Wang ◽

Ju-Yeon Choi ◽

Myong-Cheol Lim ◽

Jung-Hye Choi

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Cell Invasion ◽

Ovarian Cancer Cell ◽

Ovarian Cancer Cells ◽

Human Ovarian Cancer ◽

Cancer Cell Invasion ◽

Cc Chemokine ◽

Chemokine Ligand

In the tumor microenvironment, macrophages have been suggested to be stimulated by tumor cells, becoming tumor-associated macrophages that promote cancer development and progression. We examined the effect of these macrophages on human ovarian cancer cell invasion and found that conditioned medium of macrophages stimulated by ovarian cancer cells (OC-MQs) significantly increased cell invasion. CC chemokine ligand 7 (CCL7) expression and production were significantly higher in OC-MQs than in the control macrophages. Peritoneal macrophages from patients with ovarian cancer showed higher CCL7 expression levels than those from healthy controls. Inhibition of CCL7 using siRNA and neutralizing antibodies reduced the OC-MQ-CM-induced ovarian cancer cell invasion. CC chemokine receptor 3 (CCR3) was highly expressed in human ovarian cancer cells, and a specific inhibitor of this receptor reduced the OC-MQ-CM-induced invasion. Specific signaling and transcription factors were associated with enhanced CCL7 expression in OC-MQs. CCL7-induced invasion required the expression of matrix metalloproteinase 9 via activation of extracellular signal-related kinase signaling in human ovarian cancer cells. These data suggest that tumor-associated macrophages can affect human ovarian cancer metastasis via the CCL7/CCR3 axis.

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