Integrin signaling inhibits paclitaxel-induced apoptosis in breast cancer cells

Abstract

Inherent or acquired drug resistance is one of the major problems in chemotherapy. The mechanisms by which cancer cells survive and escape the cytotoxic e ects of chemotherapeutic agents are essentially unknown. In the present study, we demonstrate that in the MDA-MB-231 and MDA-MB-435 breast cancer cells, ligation of b1 integrins by their extracellular matrix ligands inhibits signi®cantly apoptosis induced by paclitaxel and vincristine, two microtubule-directed chemotherapeutic agents that are widely used in the therapy of breast cancer. We show that b1 integrin signaling inhibits drug-induced apoptosis by inhibiting the release of cytochrome c from the mitochondria in response to drug treatment. Further, integrin-mediated protection from drug-induced apoptosis and inhibition of cytochrome c release are dependent on the activation of the PI 3-kinase/Akt pathway. Our results identify b1 integrin signaling as an important survival pathway in drug-induced apoptosis in breast cancer cells and suggest that activation of this pathway may contribute to the generation of drug resistance. Oncogene (2001) 20, 4995 ± 5004.

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

“…Indeed, the results reported here supported such a contention by demonstrating the increased resistance of TG2-rich MDA231/cl.16 cells to paclitaxel compared with low TG2-expressing MDA231/cl.9 cells (Figure 3b). A similar resistance to paclitaxel-induced cytotoxicity has been reported by Aoudjit and Vuori (2001) in MDA-MB231 cells cultured on Fn-coated surfaces. Notably, the inhibition of TG2 protein by siRNA rendered the cells sensitive to apoptosis under serum-free conditions (Figure 7b).…”

“…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).…”

ECM overrides DNA damage-induced cell cycle arrest and apoptosis in small-cell lung cancer cells through β1 integrin-dependent activation of PI3-kinase

“…Our work and results from other groups show that a number of cancers, including SCLC, breast, prostate, colon cancer and hematological malignancies, all use ECM adhesion for survival to evade the cytotoxic effects of chemotherapy or radiotherapy. 3,[5][6][7] While this appears to be a general and important phenomenon, the actual intracellular mechanisms coupling integrin activation to protection from chemotherapy-and radiotherapy-induced apoptosis may be cancer cell type specific. The mechanisms described here for SCLC differ from those reported previously, particularly myeloma cells.…”

“…Apoptosis was assessed 0-72 h later by the addition of 1 ml of ethidium bromide (1 mg/ml) (Sigma) and 1 ml acridine orange (1 mg/ml) (Sigma) and the percentage of apoptotic cells was determined by fluorescent microscopy as described previously. 5 Apoptosis was also determined using a cell death detection ELISAt kit (based on the quantitative detection of histone-associated DNA fragments in mono-and oligonucleosomes) according to the manufacturer's instructions (Roche Diagnostics) and by flow-cytometric analysis of Annexin V staining according to the manufacturer's instructions (Annexin V-PE BD Bioscience).…”

“…3 This has now been demonstrated to be a general mechanism for acquired drug resistance in a number of malignancies including myeloma, breast and colon cancer. 3,[5][6][7] However, the intracellular signals activated by ECM components in cancer cells, which influence response to chemotherapy and radiotherapy, have not been fully elucidated. A clear understanding of these mechanisms is essential to the development of rational therapeutic strategies to overcome acquired MDR and enhance the effects of chemotherapy and radiotherapy.…”