Fibronectin and laminin increase resistance to ionizing radiation and the cytotoxic drug Ukrain^®in human tumour and normal cellsin vitro

Abstract

The data corroborate the findings of other groups that cell adhesion-mediated resistance to either single or combined drug and radiation exposure is tightly correlated to specific ECM proteins. By demonstrating a strong modulatory impact of FN and LA on the radiosensitivity-modifying activity of the drug Ukrain, the set findings are also highly important for the assessment of drug and radiation effects within in vitro cytotoxicity studies. The data give the first mechanistic insights into specific FN- and LA-modulated cellular resistance mechanisms as well as into the important role for beta1-integrins using the unique cytotoxic and radiosensitivity-modifying drug Ukrain.

Tissue transglutaminase expression promotes cell attachment, invasion and survival in breast cancer cells

“…These results suggest that TG2 expression in cancer cells promotes cell surface interaction with Fn and protects cells from apoptosis. Indeed, it has been well documented that the interaction of cancer cells with Fn can induce cell survival signaling pathways and confer chemoresistance (Zhang et al, 1995;Damiano et al, 1999;Cordes et al, 2003). Because cell surface TG2 is responsible for mediating the interaction of integrins with Fn by acting as a coreceptor for the extracellular matrix (ECM) ligand, we next determined the levels of cell surface TG2 and integrins in the parental and MDA-MB231 sublines.…”

“…For example, the culture of a5b1-integrinexpressing cells on Fn is associated with increased expression of the antiapoptotic protein Bcl2 and thus protects these cells from apoptosis (Zhang et al, 1995). Similarly, several cancer cell lines have been shown to better survive chemotherapy or radiation-induced cell death when cultured on Fn-coated surfaces (Damiano et al, 1999(Damiano et al, , 2001Aoudjit and Vuori, 2001;Cordes et al, 2003;Korah et al, 2004). The crosstalk between the cell surface a5b1-integrin and Fn leads to the activation of signaling pathways that can induce cell growth and contribute to the development of the metastatic phenotype (Parise et al, 2000;Mehlen and Puisieux, 2006).…”

Implications of increased tissue transglutaminase (TG2) expression in drug-resistant breast cancer (MCF-7) cells

“…In view of our observations that drugresistant MCF-7 cells, in addition toTG2, also expressed high levels of a5b1 and a4b1 (ligands for Fn) and the earlier observations that TG2 has a high-binding affinity for Fn (Jeong et al, 1995), we postulated that TG2 promotes the a4b1 as well as a5b1-mediated interaction of cells to Fn in the ECM and thus induce cell survival signaling pathways. Indeed, interaction of cancer cells with Fn has been shown to promote the cell survival signaling pathways and confer resistance to chemotherapeutic drugs (Zhang et al, 1995;Damiano et al, 1999Damiano et al, , 2001Mauro et al, 1999;Aoudjit and Vuori, 2001;de la Fuente et al, 2002;Cordes et al, 2003;Korah et al, 2004). The 'open' curve shows the fluorescence intensity of integrins as revealed by immunostaining of cells with specific integrin antibody, followed by the flurochrome Alex-488-conjugated secondary antibody as described in Materials and methods.…”

“…For example, culture of a5b1 integrin-expressing cells on Fn is associated with the increased expression of antiapoptotic protein Bcl 2 and with protection from apoptosis (Zhang et al, 1995). Similarly, several cancer cell lines have been shown to better survive the chemotherapy or radiation-induced cytotoxic effects when cultured on Fn-coated surfaces (Damiano et al, 1999(Damiano et al, , 2001Aoudjit and Vuori, 2001;de la Fuente et al, 2002;Cordes et al, 2003;Korah et al, 2004). Interestingly, the metastatic breast cancer cells MDA-MB-231, which exhibit resistance to chemotherapy (Aoudjit and Vuori, 2001) At 48 h after transfection with control or TG2-specific siRNAs the MCF-7/RT cells were plated (5 Â 10 3 cells/0.2 ml/well) in quadruplicates in 96-well plate.…”

Studies of the in vivo radiosensitivity of human skin fibroblasts

“…It is possible, however, that the in situ microenvironment of the dermal fibroblast might affect their radiosensitivity by a mechanism not present in culture. Recent work has suggested that integrin signaling, such as may occur in interaction between cells and the extracellular matrix can affect radiosensitivity [8]. Thus we were interested to study the radiosensitivity of the dermal fibroblasts irradiated in situ.…”