β1 Integrins as Therapeutic Targets to Disrupt Hallmarks of Cancer

Blandin, Anne-Florence; Renner, Guillaume; Lehmann, Maxime; Lelong-Rebel, Isabelle; Martin, Sophie; Dontenwill, Monique

doi:10.3389/fphar.2015.00279

Cited by 91 publications

(92 citation statements)

References 145 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The interaction of extracellular matrix macromolecules and their cell surface receptors, in particular, integrins, contribute to cell proliferation in physiological and pathological conditions333435. This is realized by the cross-talk between integrins and growth factor receptors, regulatory loop between integrin/FAK and tumor suppressor p53, and integrin-dependent signaling pathways such as PI3K/Akt/mTOR, NF-κB, and MEK/ERK.…”

Section: Discussionmentioning

confidence: 99%

Extracellular matrix protein Reelin promotes myeloma progression by facilitating tumor cell proliferation and glycolysis

Qin

Lin

Cao

et al. 2017

Sci Rep

View full text Add to dashboard Cite

Reelin is an extracellular matrix protein that is crucial for neuron migration, adhesion, and positioning. We examined the expression of Reelin in a large cohort of multiple myeloma patients recorded in Gene Expression Omnibus (GEO) database and used over-expression and siRNA knockdown of Reelin to investigate the role of Reelin in myeloma cell growth. We find that Reelin expression is negatively associated with myeloma prognosis. Reelin promotes myeloma cell proliferation in vitro as well as in vivo. The Warburg effect, evidenced by increased glucose uptake and lactate production, is also enhanced in Reelin-expressing cells. The activation of FAK/Syk/Akt/mTOR and STAT3 pathways contributes to Reelin-induced cancer cell growth and metabolic reprogramming. Our findings further reveal that activated Akt and STAT3 pathways induce the upregulation of HIF1α and its downstream targets (LDHA and PDK1), leading to increased glycolysis in myeloma cells. Together, our results demonstrate the critical contributions of Reelin to myeloma growth and metabolism. It presents an opportunity for myeloma therapeutic intervention by inhibiting Reelin and its signaling pathways.

show abstract

Section: Discussionmentioning

confidence: 99%

Extracellular matrix protein Reelin promotes myeloma progression by facilitating tumor cell proliferation and glycolysis

Qin

Lin

Cao

et al. 2017

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Together, this strongly suggests that Epac-Rap1-mediated survival signals are mediated by integrin-binding to RGD-containing ligands resulting in acquired triapine resistance. In line with this observation, several studies reported a role of altered integrin expression and especially subunit β1 in resistance against diverse cancer therapeutics in solid tumors [34]. For example, temozolomide resistance in glioblastoma [63] and vemurafenib resistance in melanoma are mediated via α5β1 integrin-dimer [64], while doxorubicin resistance in leukemia seems to be promoted by α2β1 [65].…”

Section: Discussionmentioning

confidence: 92%

Loss of phosphodiesterase 4D mediates acquired triapine resistance via Epac-Rap1-Integrin signaling

et al. 2016

View full text Add to dashboard Cite

Triapine, an anticancer thiosemicarbazone, is currently under clinical investigation. Whereas promising results were obtained in hematological diseases, trials in solid tumors widely failed. To understand mechanisms causing triapine insensitivity, we have analysed genomic alterations in a triapine-resistant SW480 subline (SW480/tria). Only one distinct genomic loss was observed specifically in SW480/tria cells affecting the phosphodiesterase 4D (PDE4D) gene locus. Accordingly, pharmacological inhibition of PDE4D resulted in significant triapine resistance in SW480 cells. Hence, we concluded that enhanced cyclic AMP levels might confer protection against triapine. Indeed, hyperactivation of both major downstream pathways, namely the protein kinase A (PKA)-cAMP response element-binding protein (Creb) and the exchange protein activated by cAMP (Epac)-Ras-related protein 1 (Rap1) signaling axes, was observed in SW480/tria cells. Unexpectedly, inhibition of PKA did not re-sensitize SW480/tria cells against triapine. In contrast, Epac activation resulted in distinct triapine resistance in SW480 cells. Conversely, knock-down of Epac expression and pharmacological inhibition of Rap1 re-sensitized SW480/tria cells against triapine. Rap1 is a well-known regulator of integrins. Accordingly, SW480/tria cells displayed enhanced plasma membrane expression of several integrin subunits, enhanced adhesion especially to RGD-containing matrix components, and bolstered activation/expression of the integrin downstream effectors Src and RhoA/Rac. Accordingly, integrin and Src inhibition resulted in potent triapine re-sensitization especially of SW480/tria cells. In summary, we describe for the first time integrin activation based on cAMP-Epac-Rap1 signaling as acquired drug resistance mechanism. combinations of triapine with inhibitors of several steps in this resistance cascade might be feasible strategies to overcome triapine insensitivity of solid tumors.

show abstract

“…and ultimately leads to cell apoptosis. [47] Thus, the understanding of CAM-DR mechanisms and elucidation the roles of FN1 and integrins such as ITGA1, ITGA5, and ITGA6 may offer valuable therapeutic approaches for drug-resistant ovarian cancer.…”

Section: Discussionmentioning

confidence: 99%

STROBE-compliant integrin through focal adhesion involve in cancer stem cell and multidrug resistance of ovarian cancer

et al. 2017

View full text Add to dashboard Cite

Cancer stem cells (CSCs) are considered to be the root of carcinoma relapse and drug resistance in ovarian cancer. Hunting for the potential CSC genes and explain their functions would be a feasible strategy to meet the challenge of the drug resistance in ovarian cancer. In this study, we performed bioinformatic approaches such as biochip data extraction and pathway enrichment analyses to elucidate the mechanism of the CSC genes in regulation of drug resistance. Potential key genes, integrins, were identified to be related to CSC in addition to their associations with drug resistance and prognosis in ovarian cancer. A total of 36 ovarian CSC genes involved in regulation of drug resistance were summarized, and potential drug resistance-related CSC genes were identified based on 3 independent microarrays retrieved from the Gene Expression Omnibus (GEO) Profiles. Pathway enrichment of CSC genes associated with drug resistance in ovarian cancer indicated that focal adhesion signaling might play important roles in CSC genes-mediated drug resistance. Integrins are members of the adhesion molecules family, and integrin subunit alpha 1, integrin subunit alpha 5, and integrin subunit alpha 6 (ITGA6) were identified as central CSC genes and their expression in side population cells, cisplatin-resistant SKOV3 (SKOV3/DDP2) cells, and cisplatin-resistant A2780 (A2780/DDP) cells were dysregulated as measured by real-time quantitative polymerase chain reaction. The high expression of ITGA6 in 287 ovarian cancer patients of TCGA cohort was significantly associated with poorer progression-free survival. This study provide the basis for further understanding of CSC genes in regulation of drug resistance in ovarian cancer, and integrins could be a potential biomarker for prognosis of ovarian cancer.

show abstract

β1 Integrins as Therapeutic Targets to Disrupt Hallmarks of Cancer

Cited by 91 publications

References 145 publications

Extracellular matrix protein Reelin promotes myeloma progression by facilitating tumor cell proliferation and glycolysis

Extracellular matrix protein Reelin promotes myeloma progression by facilitating tumor cell proliferation and glycolysis

Loss of phosphodiesterase 4D mediates acquired triapine resistance via Epac-Rap1-Integrin signaling

STROBE-compliant integrin through focal adhesion involve in cancer stem cell and multidrug resistance of ovarian cancer

Contact Info

Product

Resources

About