Expression of focal adhesion kinase in uveal melanoma and the effects of Hsp90 inhibition by 17-AAG

Faingold, D.; Bravo-Filho, Vasco; Fernandes, Bruno F.; Jagan, Lisa; Barros, Alexandre M. de; Orellana, María Eugenia; Antecka, E.; Burnier, Miguel N.

doi:10.1016/j.prp.2014.06.023

Cited by 8 publications

(10 citation statements)

References 30 publications

(44 reference statements)

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“…The used methods are described in the legend of Figure 2 and Figure A1. Based on this Pubmed search, we found an overexpression of FAK at the protein level, as evaluated by IHC, in 80% of pancreatic adenocarcinoma, 72% of neuroblastoma, 70% of ovarian epithelial tumors, and many other cancers, including 52% of NSCLC and 69% of SCLC (Figure 2) [20,21,24,26,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109].…”

Section: Fak Overexpression And/or Activation In Human Cancers Itmentioning

confidence: 99%

Role of Focal Adhesion Kinase in Small-Cell Lung Cancer and Its Potential as a Therapeutic Target

Nana

Vanderputten

Ocak

2019

Cancers

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Small-cell lung cancer (SCLC) represents 15% of all lung cancers and it is clinically the most aggressive type, being characterized by a tendency for early metastasis, with two-thirds of the patients diagnosed with an extensive stage (ES) disease and a five-year overall survival (OS) as low as 5%. There are still no effective targeted therapies in SCLC despite improved understanding of the molecular steps leading to SCLC development and progression these last years. After four decades, the only modest improvement in OS of patients suffering from ES-SCLC has recently been shown in a trial combining atezolizumab, an anti-PD-L1 immune checkpoint inhibitor, with carboplatin and etoposide, chemotherapy agents. This highlights the need to pursue research efforts in this field. Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase that is overexpressed and activated in several cancers, including SCLC, and contributing to cancer progression and metastasis through its important role in cell proliferation, survival, adhesion, spreading, migration, and invasion. FAK also plays a role in tumor immune evasion, epithelial-mesenchymal transition, DNA damage repair, radioresistance, and regulation of cancer stem cells. FAK is of particular interest in SCLC, being known for its aggressiveness. The inhibition of FAK in SCLC cell lines demonstrated significative decrease in cell proliferation, invasion, and migration, and induced cell cycle arrest and apoptosis. In this review, we will focus on the role of FAK in cancer cells and their microenvironment, and its potential as a therapeutic target in SCLC.

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Section: Fak Overexpression And/or Activation In Human Cancers Itmentioning

confidence: 99%

Role of Focal Adhesion Kinase in Small-Cell Lung Cancer and Its Potential as a Therapeutic Target

Nana

Vanderputten

Ocak

2019

Cancers

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“…Thus, it is of great bene t to fully investigate the biological basis for PTK2 over-activation, facilitating the future development of novel therapeutic targeted drugs. Recently, Faingold et al found that Hsp90 maybe a regulator for PTK2 expression and activation (24). Gangemi et al demonstrated that Mda-9/syntenin could promote the cell motility and invasion capacity through connecting surface integrin signals to PTK2 activity (26).…”

Section: Discussionmentioning

confidence: 99%

PTK2 Promotes Uveal Melanoma Metastasis by Activating Epithelial-to-Mesenchymal Transition

Fan

Duan

Zhang

et al. 2021

Preprint

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Background: Uveal melanoma (UM) is an aggressive primary intraocular tumor in adults, with high metastatic capacity and high morbidity. However, the mechanisms of UM metastasis have not been clearly elucidated.Methods: The PTK2 expression and activation were performed in the Cancer Genome Atlas (TCGA) database and 25 patients of UM. The role of PTK2 in promoting metastasis was explored in vitro and in vivo. Subsequently, we revealed the correlation between PTK2 expression and epithelial-to-mesenchymal transition (EMT). Finally, we explored the reason for the high expression of PTK2 in UM.Results: Our study found that protein tyrosine kinase 2 (PTK2) was overexpressed in UM specimens, and as a novel independent risk factor, its overexpression predicted the poor survival of UM patients. For the molecular mechanism, PTK2 promoted EMT phenotype, thus leading to tumor metastasis in UM cells. Subsequently, we have demonstrated that PTK2 was a functional gene of chromosome 8q gain accounting for UM metastasis, providing a novel molecular mechanism for the aberrantly expression and activation of PTK2 in UM.Conclusion: Our data reveal the important role and mechanism of PTK2 in the metastatic process of UM, which may clue to a new predictive biomarker for UM metastasis and a new therapeutic target for UM treatment.

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“…Calpain can also modulate invasion by regulating matrix metalloproteinase 2 (MMP-2) expression (41). Importantly, several of these calpain substrates are also HSP90 clients, including vimentin, MMP-2, and FAK (42,43). Thus, combined inhibition of calpain and HSP90 may yield additive or synergistic effects on cell death, migration, invasion, tumor growth, and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Calpain Genetic Disruption and HSP90 Inhibition Combine To Attenuate Mammary Tumorigenesis

Grieve

Gao

Hall

et al. 2016

Molecular and Cellular Biology

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Calpain is an intracellular Ca 2؉ -regulated protease system whose substrates include proteins involved in proliferation, survival, migration, invasion, and sensitivity to therapeutic drugs. Genetic disruption of calpain attenuated the tumorigenic potential of breast cancer cells and hypersensitized cells to 17AAG, an inhibitor of the molecular chaperone HSP90. Calpain-1 or -2 overexpression rendered cells resistant to 17AAG, whereas downregulation or inhibition of calpain-1/2 led to increased cell death in multiple breast cancer cell lines, including models of HER2 ؉ (SKBR3) and triple-negative basal-cell-like (MDA-MB-231) breast cancer. In an MDA-MB-231 orthotopic xenograft model, calpain knockdown or 17AAG treatment independently attenuated tumor growth and metastasis, while the combination was most effective. Calpain knockdown was associated with increased 17AAG-induced degradation of the HSP90 clients cyclin D1 and AKT and multidrug resistance protein 2, which correlated with increased expression of antimitogenic p27 KIP1 and proapoptotic BIM proteins. Like other therapeutics, 17AAG can be effluxed by specific ABC transporters. Calpain expression positively correlated with the expression of P glycoprotein in mouse embryonic fibroblasts. Importantly, we show that calpain affects ABC transporter function and efflux of clinically relevant doxorubicin. These observations provide a compelling rationale for exploring the combination of calpain inhibition with new or existing cancer therapeutics. Calpains are a family of intracellular calcium-dependent proteases. Of the 15 mammalian isoforms, calpain-1 and calpain-2 are ubiquitously expressed and have been most extensively studied (reviewed in reference 1). They are heterodimers consisting of isoform-specific catalytic subunits encoded by CAPN1 and CAPN2, respectively, and a common regulatory subunit encoded by CAPNS1. Heterodimerization is essential for both stability and enzymatic activity; hence, genetic disruption of CAPNS1 results in loss of both calpain-1 and -2 activities (2, 3).Elevated calpain expression or activity has been associated with multiple cancer types, including colon, liver, lung, prostate, ovarian, and breast cancers (reviewed in reference 4). Mechanistic understanding of calpain's involvement in cancer is confounded by its broad range of substrates, including signaling or structural proteins that regulate diverse cellular functions such as mitogenesis, migration, invasion, and death (1). Biomarker studies suggest a positive correlation between elevated calpain expression and a poor clinical outcome in breast cancer (5-7).Paradoxically, calpain is associated with prodeath (8, 9) or prosurvival (9-11), depending upon the physiologic context and specific challenges cells are exposed to. For example, calpain-mediated cleavage of PP2A supports activation of AKT and a prosurvival function in mouse embryonic fibroblasts (MEFs) (10), and in breast cancer cells and xenograft mouse models, knockdown of CAPN2 was associated with attenuated tumor growth...

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Expression of focal adhesion kinase in uveal melanoma and the effects of Hsp90 inhibition by 17-AAG

Cited by 8 publications

References 30 publications

Role of Focal Adhesion Kinase in Small-Cell Lung Cancer and Its Potential as a Therapeutic Target

Role of Focal Adhesion Kinase in Small-Cell Lung Cancer and Its Potential as a Therapeutic Target

PTK2 Promotes Uveal Melanoma Metastasis by Activating Epithelial-to-Mesenchymal Transition

Calpain Genetic Disruption and HSP90 Inhibition Combine To Attenuate Mammary Tumorigenesis

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