α2β1 Integrin Promotes Chemoresistance against Doxorubicin in Cancer Cells through Extracellular Signal-regulated Kinase (ERK)

Naci, Dalila; Azreq, Mohammed Amine El; Chetoui, Nizar; Lauden, Laura; Sigaux, François; Charron, Dominique; Al-Daccak, Reem; Aoudjit, Fawzi

doi:10.1074/jbc.m112.349365

Cited by 88 publications

(77 citation statements)

References 49 publications

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“…CTSS increases expression of MET, EGFR, ITGA2, and MMP3 (54). In turn, MET activates PI3K (76); ITGA2 activates MAPK (77), and both molecules are also activated by EGFR (78). SERPINI1 is an inhibitor of tissue plasminogen activator (tPA) (57), which inhibits ITGB1 (79).…”

Section: Discussionmentioning

confidence: 99%

In-depth Characterization of the Secretome of Colorectal Cancer Metastatic Cells Identifies Key Proteins in Cell Adhesion, Migration, and Invasion

Barderas

Mendes

Torres

et al. 2013

Molecular & Cellular Proteomics

101

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Liver metastasis in colorectal cancer is the major cause of cancer-related deaths. To identify and characterize proteins associated with colon cancer metastasis, we have compared the conditioned serum-free medium of highly metastatic KM12SM colorectal cancer cells with the parental, poorly metastatic KM12C cells using quantitative stable isotope labeling by amino acids in cell culture (SILAC) analyses on a linear ion trap-Orbitrap Velos mass spectrometer. In total, 1337 proteins were simultaneously identified in SILAC forward and reverse experiments. For quantification, 1098 proteins were selected in both experiments, with 155 proteins showing >1.5-fold change. About 52% of these proteins were secreted directly or using alternative secretion pathways. GDF15, S100A8/A9, and SERPINI1 showed capacity to discriminate cancer serum samples from healthy controls using ELISAs. In silico analyses of deregulated proteins in the secretome of metastatic cells showed a major abundance of proteins involved in cell adhesion, migration, and invasion. To characterize the tumorigenic and metastatic properties of some top up-and down-regulated proteins, we used siRNA silencing and antibody blocking. Knockdown expression of NEO1, SERPINI1, and PODXL showed a significant effect on cellular adhesion. Silencing or blocking experiments with SOSTDC1, CTSS, EFNA3, CD137L/ TNFSF9, ZG16B, and Midkine caused a significant decrease in migration and invasion of highly metastatic cells. In addition, silencing of SOSTDC1, EFNA3, and CD137L/TNFSF9 reduced liver colonization capacity of KM12SM cells. Finally, the panel of six proteins involved in invasion showed association with poor prognosis and overall survival after dataset analysis of gene alterations. In summary, we have defined a collection of proteins that are relevant for understanding the mechanisms underlying adhesion, migration, invasion, and metastasis in colorectal cancer. Molecular & Cellular

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Section: Discussionmentioning

confidence: 99%

In-depth Characterization of the Secretome of Colorectal Cancer Metastatic Cells Identifies Key Proteins in Cell Adhesion, Migration, and Invasion

Barderas

Mendes

Torres

et al. 2013

Molecular & Cellular Proteomics

101

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“…However, chemoresistance upon adhesion to substrates engaging other integrins, including ␣5, ␣6, and ␣2 (6)(7)(8)17), hints at the generality of this phenomenon. A common denominator for these ␣-integrins is their pairing with ␤1, without which the adhesion receptor is incomplete.…”

Section: Discussionmentioning

confidence: 99%

“…Cell adhesion mediated via ␣4-integrins also contributes to chemoresistance (3,4,9), which can be overcome by neutralization of the extracellular ␣4-integrin-substrate interactions (5,(14)(15)(16). However, adhesion via integrins other than ␣4 that are expressed by lymphocytes also contributes to chemoresistance (6)(7)(8)17), suggesting a common regulatory mechanism governed by integrin-mediated adhesion as the chemoprotective switch. The adhesion-mediated chemoresistance is often attributed to ␤1-integrin-mediated stimulation of Akt activity and subsequent regulation of prosurvival signaling (3,18,19).…”

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confidence: 99%

The Membrane-Proximal KXGFFKR Motif of α-Integrin Mediates Chemoresistance

Liu¹,

Leclair

Yap

et al. 2013

Molecular and Cellular Biology

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Cell adhesion-mediated drug resistance contributes to minimal residual disease and relapse in hematological malignancies. Here, we show that adhesion of Jurkat T-acute lymphoblastic leukemia cells to substrates engaging ␣4␤1-integrin or ␣5␤1-integrin promotes chemoresistance to doxorubicin-induced apoptosis. Reconstituted expression of ␣4␦, a truncated ␣4-integrin with KXGFFKR as the cytoplasmic motif, in ␣4-deficient cells promoted chemoresistance to doxorubicin in a manner independent of ␣4-mediated adhesion. The adhesion-independent chemoresistance did not require ␤1-integrin as the heterodimeric pair, since expression of Tac␦, a monomeric nonintegrin transmembrane protein fused to the juxtamembrane KXGFFKR, was sufficient to reproduce the phenomenon. The requirement for integrin-mediated adhesion in stimulation of Akt phosphorylation and activation was bypassed for cells expressing ␣4␦ and Tac␦. Cells expressing ␣4␦ and Tac␦ exhibited a high influx of extracellular Ca 2؉ , and inhibition of Ca 2؉ channels with verapamil attenuated the adhesion-independent chemoresistance. Tac␦ cells also exhibited greater rates of drug efflux. ␣4␦ and Tac␦ interacted with the Ca 2؉ -binding protein calreticulin, in a manner dependent on the KXGFFKR motif. Adhesion-mediated engagement of ␣4-integrins promoted an increased calreticulin-␣4 association and greater influx of extracellular Ca 2؉ than in nonadherent cells. The ␣-integrin KXGFFKR motif is involved in adhesion-mediated control of chemoresistance in T cells.

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“…MDR involves genetic and epigenetic dysregulation of a wide range of genes and may be caused by drug efflux transporters such as P-glycoprotein [2], breast cancer resistant protein (BCRP) or multiple resistance protein-1 (MRP1). In addition, inactivation by detoxification enzymes, the altered expression of pro-apoptosis and tumor suppressor genes, or the increased activity of DNA repair mechanisms are frequently involved [3,4]. Recent evidence indicates that microRNAs (miRNAs) regulate these processes [5,6].…”

mentioning

confidence: 99%

miR-218 targets survivin and regulates resistance to chemotherapeutics in breast cancer

Yagüe

2015

Breast Cancer Res Treat

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Multidrug resistance (MDR) remains one of the most significant obstacles in breast cancer treatment, and this process often involves dysregulation of a great number of microRNAs (miRNAs). Some miRNAs are indicators of drug resistance and confer resistance to chemotherapeutic drugs, although our understanding of this complex process is still incomplete. We have used a combination of miRNA profiling and real-time PCR in two drug-resistant derivatives of MCF-7 and Cal51 cells. Experimental modulation of miR expression has been obtained by retroviral transfection. Taxol and doxorubicin IC50 values were obtained by short-term drug sensitivity assays. Apoptosis was determined by flow cytometry after annexin V staining, by caspase 3/7 and caspase 9 activity assays and the levels of apoptosis-related proteins bcl-2 and bax by real-time PCR and Western blot. miR target was studied using transient transfection of luciferase constructs with the 3 untranslated regions (UTR) of target mRNAs. Small interfering RNA-mediated genetic knock-down was performed in MDR cells and its modulatory effect on apoptosis examined. The effect of miRNA on tumorigenicity and tumor drug response was studied in mouse xenografts. miRNA profiling of two drug-resistant breast cancer cell models indicated that miR-218 was down-regulated in both MCF-7/A02 and CALDOX cells. Ectopic expression of miR-218 resensitized both drug-resistant cell lines to doxorubicin and taxol due to an increase in apoptosis. miR-218 binds survivin (BIRC5) mRNA 3-UTR and down-regulated reporter luciferase activity. Experimental down-regulation of survivin by RNA interference in drug-resistant cells did mimic the sensitization observed when miRNA-218 was up-regulated. In addition, resensitization to taxol was also observed in mouse tumor xenografts from cells over-expressing miR-218. miR-218 is involved in the development of MDR in breast cancer cells via targeting survivin and leading to evasion of apoptosis. Targeting miR-218 and survivin may thus provide a potential strategy for reversing drug resistance in breast cancer

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α2β1 Integrin Promotes Chemoresistance against Doxorubicin in Cancer Cells through Extracellular Signal-regulated Kinase (ERK)

Cited by 88 publications

References 49 publications

In-depth Characterization of the Secretome of Colorectal Cancer Metastatic Cells Identifies Key Proteins in Cell Adhesion, Migration, and Invasion

In-depth Characterization of the Secretome of Colorectal Cancer Metastatic Cells Identifies Key Proteins in Cell Adhesion, Migration, and Invasion

The Membrane-Proximal KXGFFKR Motif of α-Integrin Mediates Chemoresistance

miR-218 targets survivin and regulates resistance to chemotherapeutics in breast cancer

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