Adhesion to fibronectin via β1 integrins regulates p27kip1 levels and contributes to cell adhesion mediated drug resistance (CAM-DR)

Hazlehurst, Lori A.; Damiano, Jason S.; Buyuksal, I; Pledger, W. J.; Dalton, William S.

doi:10.1038/sj.onc.1203782

Cited by 309 publications

(271 citation statements)

References 56 publications

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“…Previous studies in hemapoeitic tumor cells have demonstrated that adhesion to fibronectin protected against chemotherapeutic agents through increased expression of p27 Kip1 and G1 cell cycle arrest. 30 Furthermore, integrin-mediated adhesion in hemapoeitic cancer cells reduced DNA double-strand breaks and apoptosis caused by chemotherapeutic agents such as mitoxantrone and etoposide. 31 This primarily a5b1-mediated reduction in DNA damage correlated with decreased topoisomerase-II enzymatic activity.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2006

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The emergence of resistance to chemotherapy remains a principle problem in the treatment of small-cell lung cancer (SCLC). We demonstrate that extracellular matrix (ECM) activates phosphatidyl inositol 3-kinase (PI3-kinase) signaling in SCLC cells and prevents etoposide-induced caspase-3 activation and subsequent apoptosis in a b1 integrin/PI3-kinase-dependent manner. Crucially we show that etoposide and radiation induce G2/M cell cycle arrest in SCLC cells prior to apoptosis and that ECM prevents this by overriding the upregulation of p21 Cip1/WAF1 and p27 Kip1 and the downregulation of cyclins E, A and B. These effects are abrogated by pharmacological and genetic inhibition of PI3-kinase signaling. Importantly we show that chemoprotection is not mediated by altered SCLC cell proliferation or DNA repair. Thus, ECM via b1 integrin-mediated PI3-kinase activation overrides treatment-induced cell cycle arrest and apoptosis, allowing SCLC cells to survive with persistent DNA damage, providing a model to account for the emergence of acquired drug resistance.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2006

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“…Furthermore, the ECM might have a great impact on the cellular responsiveness to external stimuli. Published in vitro and in vivo findings showed the importance of the extracellular environment on drug (Sethi et al, 1999;Hazlehurst et al, 2000) and radiation sensitivity (Vlodavsky et al, 1980;Cordes and Meineke, in press;Cordes et al, in press), conferring resistance to DNA-damaging agents. Since integrin and growth factor receptors are colocalised at the source of integrin signalling, which are called focal adhesions, convergence and mutual modification between these networks are highly likely to occur.…”

Section: Discussionmentioning

confidence: 99%

“…The presence of extracellular matrix (ECM) increases cellular resistance to cell-damaging agents such as drugs or ionising radiation (Damiano et al, 1999;Rose et al, 1999;Hazlehurst et al, 2000;Cordes and Meineke, in press;Cordes et al, in press). For the treatment of cells with cytotoxic agents in the presence of ECM, the convergence of integrin-related and cell cycle-related signal transduction pathways could be of great importance.…”

mentioning

confidence: 99%

“…For the treatment of cells with cytotoxic agents in the presence of ECM, the convergence of integrin-related and cell cycle-related signal transduction pathways could be of great importance. Possible interactions of these pathways are likely to be modulated by the ECM and, thus, may play an important role in resistance-mediating mechanisms (Sethi et al, 1999;Hazlehurst et al, 2000), anchorage-independent cell growth (Shin et al, 1975;Radeva et al, 1997), oncogenic transformation (White et al, 2001), the assessment of in vitro cytotoxicity studies, and new strategies for controlling and healing cancer.…”

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confidence: 99%

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Cell adhesion to the extracellular matrix protein fibronectin modulates radiation-dependent G2 phase arrest involving integrin-linked kinase (ILK) and glycogen synthase kinase-3β (GSK-3β) in vitro

Cordes

Beuningen

2003

Br J Cancer

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Cell adhesion to extracellular matrix (ECM) is thought to confer resistance against cell-damaging agents, that is, drugs and radiation, in tumour and normal cells in vitro. The dependence of cell survival on b1-integrin-linked kinase (ILK), protein kinase Ba/Akt (PKBa/Akt) and glycogen synthase kinase-3b (GSK-3b) activity, which participate in b1-integrin signalling and cell cycle progression was investigated as a function of radiation exposure. Colony-formation assays on polystyrene, fibronectin (FN), laminin (LA), bovine serum albumin (BSA) or poly-L-lysine (poly-L) (0 -8 Gy), kinase assays, flow cytometric DNA and annexin-V analysis and immunoblotting were performed in nonirradiated and irradiated (2 or 6 Gy) A549 human lung cancer cells and CCD32 normal human lung fibroblasts. Cell contact to FN in contrast to polystyrene elevated basal ILK, PKBa/Akt and GSK-3b kinase activities in A549 and CCD32 cells, as well as the basal amount of A549 G2 phase cells. Irradiation on FN or LA as compared to polystyrene, BSA or poly-L significantly improved cell survival. Following irradiation, kinase activities were stimulated strongly on polystyrene but showed to be less prominent on FN, which was because of the FN-related basal induction. Following irradiation, FN compared to polystyrene enlarged and prolonged G2 arrest in both the cell lines. For the analysis of phosphatidylinositol-3 kinase (PI3-K) dependence of protein kinases and cell cycle transition, the PI3-K inhibitors LY294002 and wortmannin were used showing decreased kinase activities, antiproliferative and radiation-dependent G2 accumulation-abrogating effects accompanied by downregulation of cyclin D1 and phospho-pRb in cells attached to polystyrene. Fibronectin partly abrogated these effects PI3-Kindependently. These findings suggest a novel pathway that makes direct phosphorylation of GSK-3b by ILK feasible after irradiation. Conclusively, the data indicate that ILK, PKBa/Akt and GSK-3b are involved in modulations of the cell cycle after irradiation. These interactions are strictly dependent on ECM components in a cell line-specific manner. Our findings provide molecular insights into mechanisms likely to be important for ECM-dependent cell survival and cellular radioresistance as well as tumour growth.

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“…The MM microenvironment is formed by clonal plasma cells, ECM proteins and BMSC, which are intimately involved in all biological stages of intramedullary growth (Table 2) (Kuehl and Bersagel, 2002). Interactions between these components determine the proliferation, migration and survival of plasma cells, as well as their acquisition of drug resistance and the development of diseases (Damiano et al, 1999;Hazlehurst et al, 2000Hazlehurst et al, , 2003. Receptors expressed by plasma cells, such as a V b3 integrin, are crucial for their relationships with each other (homotypic interrelationships) and with ECM proteins (Vacca et al, 2001).…”

Section: Multiple Myeloma Microenvironmentmentioning

confidence: 99%

Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma

2006

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Tumor microenvironment is essential for tumor cell proliferation, angiogenesis, invasion and metastasis through its provision of survival signals, secretion of growth and pro-angiogenic factors, and direct adhesion molecule interactions. This review examines its importance in the induction of an angiogenic response in multiple myeloma (MM). The encouraging results of preclinical and clinical trials in which MM has been treated by targeting the tumor microenvironment are also discussed.

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Adhesion to fibronectin via β1 integrins regulates p27kip1 levels and contributes to cell adhesion mediated drug resistance (CAM-DR)

Cited by 309 publications

References 56 publications

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

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

Cell adhesion to the extracellular matrix protein fibronectin modulates radiation-dependent G2 phase arrest involving integrin-linked kinase (ILK) and glycogen synthase kinase-3β (GSK-3β) in vitro

Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma

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