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Title: Novel Mechanisms of Chmoresistance in Solid Tumours
Author: Cao, Lin
ISNI:       0000 0004 2672 5595
Awarding Body: Aberdeen University
Current Institution: University of Aberdeen
Date of Award: 2008
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Our results revealed a gene set of 15 transcripts whose expression was highly correlated with platinum-resistance in NSCLC A549 cell lines.  Among this gene set, two melanoma antigen genes, MAGEA3 and MAGEA6, were strongly downregulated in all platinum-resistant A549 cell lines (57.5 fold and 67.4 fold decrease, respectively).  Further investigation demonstrated that over-expression of MAGEA3 or MAGEA6 increased sensitivity to platinum drugs in platinum-resistant NSCLC cell lines, but not in sensitive A549 cells that already have high levels of endogenous MAGEA proteins or in CRC H630 lines. Our data suggest that lysosomal proteases and their inhibitors are not only biomarkers of platinum-resistance in NSCLC cells, but also have a functional role in resistance to these drugs in this tumour type. Our results indicate that serpinB3 plays a crucial role in platinum-resistance in NSCLC cells and lysosomal cathepsins K and L at least partly mediate the cytotoxicity of cisplatin and carboplatin, but not oxaliplatin, in NSCLC cells.  CTSB also has a critical functional role in platinum drug resistance in NSCLC A549 cell lines as an anti-apoptotic factor in response to platinums. Our data has identified novel chemoresistance biomarkers in cell lines and this correlates with molecular changes in patients not responding to therapy.  Thus these data have provided an essential prerequisite to move towards prediction of response and prognosis in cancer patients and validate these novel molecular targets for development of innovative anti-cancer therapeutics.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available