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Title: Phosphoinositide 3-kinase regulation of anchorage-independent growth and drug resistance in small cell lung cancer cells
Author: Moore, Sarah Margaret
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1999
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In this thesis it is shown that PI 3-kinase is constitutively activated in SCLC cell lines (H69, H345 and H510). Inhibition of PI 3-kinase activity using the selective inhibitors wortmannin and LY294002 markedly inhibits cell proliferation and stimulates apoptosis in liquid media. This inhibition of proliferation is shown to occur via both ribosomal protein s6 kinase (p70s6kinase) dependent and independent mechanisms. Furthermore, PI 3-kinase inhibition reduced basal SCLC cell growth in agarose semi-solid media which could not be rescued by the addition of neuropeptides. This is the first description of a constitutively activated PI 3-kinase in any human cancer. It is proposed that this constitutive activity plays an important role in promoting growth, anchorage-independence and tumorigenicity in SCLC, and may account for the non-adherent phenotype and highly metastatic nature of this cancer. Resistance to chemotherapy is a major problem in the treatment of SCLC. Adhesion to extracellular matrix (ECM) proteins can protect cells from undergoing detachment-induced apoptosis. SCLC cells in vivo are surrounded by a specialized micro-environment rich in ECM containing in part laminin, fibronectin and collagen IV. It is shown that SCLC cells adhere to the ECM proteins in vitro in a β1 integrin-dependent manner, enhancing tumourigenicity and conferring resistance to standard chemotherapeutic agents. This adhesion to ECM proteins increases SCLC cell growth and protects cells from the pro-apoptotic effects of the chemotherapy agents via a β1-integrin-dependent mechanism requiring tyrosine kinase activation. Thus ECM proteins in vivo may provide a signal resulting in resistance to chemotherapy. These findings may begin to proivde us with novel targets for the therapeutic intervention of SCLC.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available