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An altered fibronectin matrix induces anoikis of human squamous cell carcinoma cells by suppressing integrin alpha v levels and phosphorylation of FAK and ERK.
Apoptosis. 2007 Dec; 12(12):2221-31.A

Abstract

Fibronectin regulates many cellular processes, including migration, proliferation, differentiation, and survival. Previously, we showed that squamous cell carcinoma (SCC) cell aggregates escape suspension-induced, p53-mediated anoikis by engaging in fibronectin-mediated survival signals through focal adhesion kinase (FAK). Here we report that an altered matrix, consisting of a mutated, nonfunctional high-affinity heparin-binding domain and the V region of fibronectin (V+H-), induced anoikis in human SCC cells; this response was blocked by inhibitors of caspase-8 and caspase-3. Anoikis was mediated by downregulation of integrin alpha v in a panel of SCC cells and was shown to be proteasome-dependent. Overexpression of integrin alpha v or FAK inhibited the increase in caspase-3 activation and apoptosis, whereas suppression of alpha v or FAK triggered a further significant increase in apoptosis, indicating that the apoptosis was mediated by suppression of integrin alpha v levels and dephosphorylation of FAK. Treatment with V+H- decreased the phosphorylation of extracellular signal-regulated kinase (ERK) 1 and 2, and direct activation of ERK by constitutively active MEK1, an ERK kinase, increased ERK1 and ERK2 phosphorylation and inhibited the increase in apoptosis induced by V+H-. ERK acted downstream from alpha v and FAK signals, since alpha v and FAK overexpression inhibited both the decrease in ERK phosphorylation and the increase in anoikis triggered by V+H-. These findings provide evidence that mutations in the high-affinity heparin-binding domain in association with the V region of fibronectin, or altered fibronectin matrices, induce anoikis in human SCC cells by modulating integrin alpha v-mediated phosphorylation of FAK and ERK.

Authors+Show Affiliations

Department of Periodontics and Oral Medicine, University of Michigan, School of Dentistry, 1011 N. University Ave, Room 5223, Ann Arbor, MI 48109-1078, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

17879163

Citation

Kamarajan, Pachiyappan, and Yvonne L. Kapila. "An Altered Fibronectin Matrix Induces Anoikis of Human Squamous Cell Carcinoma Cells By Suppressing Integrin Alpha V Levels and Phosphorylation of FAK and ERK." Apoptosis : an International Journal On Programmed Cell Death, vol. 12, no. 12, 2007, pp. 2221-31.
Kamarajan P, Kapila YL. An altered fibronectin matrix induces anoikis of human squamous cell carcinoma cells by suppressing integrin alpha v levels and phosphorylation of FAK and ERK. Apoptosis. 2007;12(12):2221-31.
Kamarajan, P., & Kapila, Y. L. (2007). An altered fibronectin matrix induces anoikis of human squamous cell carcinoma cells by suppressing integrin alpha v levels and phosphorylation of FAK and ERK. Apoptosis : an International Journal On Programmed Cell Death, 12(12), 2221-31.
Kamarajan P, Kapila YL. An Altered Fibronectin Matrix Induces Anoikis of Human Squamous Cell Carcinoma Cells By Suppressing Integrin Alpha V Levels and Phosphorylation of FAK and ERK. Apoptosis. 2007;12(12):2221-31. PubMed PMID: 17879163.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - An altered fibronectin matrix induces anoikis of human squamous cell carcinoma cells by suppressing integrin alpha v levels and phosphorylation of FAK and ERK. AU - Kamarajan,Pachiyappan, AU - Kapila,Yvonne L, PY - 2007/9/20/pubmed PY - 2008/1/31/medline PY - 2007/9/20/entrez SP - 2221 EP - 31 JF - Apoptosis : an international journal on programmed cell death JO - Apoptosis VL - 12 IS - 12 N2 - Fibronectin regulates many cellular processes, including migration, proliferation, differentiation, and survival. Previously, we showed that squamous cell carcinoma (SCC) cell aggregates escape suspension-induced, p53-mediated anoikis by engaging in fibronectin-mediated survival signals through focal adhesion kinase (FAK). Here we report that an altered matrix, consisting of a mutated, nonfunctional high-affinity heparin-binding domain and the V region of fibronectin (V+H-), induced anoikis in human SCC cells; this response was blocked by inhibitors of caspase-8 and caspase-3. Anoikis was mediated by downregulation of integrin alpha v in a panel of SCC cells and was shown to be proteasome-dependent. Overexpression of integrin alpha v or FAK inhibited the increase in caspase-3 activation and apoptosis, whereas suppression of alpha v or FAK triggered a further significant increase in apoptosis, indicating that the apoptosis was mediated by suppression of integrin alpha v levels and dephosphorylation of FAK. Treatment with V+H- decreased the phosphorylation of extracellular signal-regulated kinase (ERK) 1 and 2, and direct activation of ERK by constitutively active MEK1, an ERK kinase, increased ERK1 and ERK2 phosphorylation and inhibited the increase in apoptosis induced by V+H-. ERK acted downstream from alpha v and FAK signals, since alpha v and FAK overexpression inhibited both the decrease in ERK phosphorylation and the increase in anoikis triggered by V+H-. These findings provide evidence that mutations in the high-affinity heparin-binding domain in association with the V region of fibronectin, or altered fibronectin matrices, induce anoikis in human SCC cells by modulating integrin alpha v-mediated phosphorylation of FAK and ERK. SN - 1360-8185 UR - https://www.unboundmedicine.com/medline/citation/17879163/An_altered_fibronectin_matrix_induces_anoikis_of_human_squamous_cell_carcinoma_cells_by_suppressing_integrin_alpha_v_levels_and_phosphorylation_of_FAK_and_ERK_ L2 - https://doi.org/10.1007/s10495-007-0138-9 DB - PRIME DP - Unbound Medicine ER -