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Title: The molecular mechanisms regulating anchorage-dependence, drug resistance and apoptosis in small cell lung cancer
Author: Rintoul, Robert C.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2001
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Phosphoinositide 3-kinase (PI 3-kinase), a regulator of multiple cellular processes including mitogenesis and invasion, is shown to be constitutively active in SCLC cell lines resulting in elevated levels of phosphatidylinositol 3,4,5 trisphosphate and protein kinase B (PKB). Inhibition of PI 3-kinase abrogated SCLC cell proliferation and colony formation and stimulated apoptosis. These data represent the first description of constitutively activated PI 3-kinase/PKB in any human cancer. Constitutive activation of PI 3-kinase may mimic integrin-dependent signal transduction thereby promoting cellular proliferation, anchorage-independence and tumourigenicity in SCLC. Tumour recurrence following chemotherapy remains a major obstacle to the cure of SCLC. We hypothesised that a factor(s) within the local environment of SCLC cells might provide a ‘survival’ signal or block a ‘death’ signal, thereby accounting for the protection of SCLC cells from chemotherapy-induced apoptosis. Integrin-dependent adhesion of SCLC cells to ECM proteins, which occur in profusion in SCLC tumours in vivo, conferred resistance to chemotherapy-induced apoptosis. ECM protein-induced tyrosine phosphorylation was found to block chemotherapy-induced activation of the ‘death’ protease capase-3 and hence, apoptosis. Survival of tumour cells attached to ECM proteins may explain the local recurrence of SCLC often seen clinically after chemotherapy. In vivo, cancer cells exist in a state of dynamic interplay between anchorage-dependence and independence. Alterations in cell adhesion and migration are dependent upon rapid, controlled alterations of the affinity of integrins for their extracellular ligands. CD98 has recently been identified as a unique and highly specific regulator of integrin affinity but its mechanism of action is not known. CD98 is highly expressed on SCLC cells both in vivo and in vitro.  PI 3-kinase and PKB could both be activated with an anti-CD98 antibody (4F2) but not with monovalent 4F2-Fab showing that cross-linking of CD98 is required for their activation. Cross-linking CD98 stimulated SCLC cell growth in Liquid culture and anchorage-independent growth in semi-solid agarose medium. These effects could be blocked by a PI 3-kinase inhibitor. This data supports the hypothesis that CD98 promotes integrin-like intracellular signalling and is able to regulate anchorage-dependence and independence.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available