Oesophageal cancer is highly resistant with a five-year survival of seventeen percent in
Ireland. We have investigated the response of oesophageal cancer cells to the
chemotherapeutic drugs, 5-fluorouracil and cisplatin. We have shown that chemosensitive
cells exhibit apoptosis whereas chemoresistant cells exhibit autophagy and limited Type II
cell death. We have undertaken gene array analysis of cells that respond to
chemotherapeutic agents by inducing predominantly apoptosis or autophagy. This has
identified a network of differentially expressed genes that function together in the
ISGylation pathway. ISGylation is a protein modification, in which the protein ISG15 is added
to target proteins, using specific E1, E2 and E3 enzymes, in a similar manner to ubiquitin. We
have already demonstrated that ISG15 and the E2 enzyme involved – UBE2L6, are negative
regulators of autophagy [1]. We also have preliminary evidence that MXA – a known target
of ISGylation – can influence cell death. Overexpression of MXA in an apoptosis
incompetent, drug resistance cell line, dramatically increased drug sensitivity – and this was
the first time we have seen an apoptosis like morphology in these cells. In this project we
will further evaluate how MXA can influence cell fate and examine whether this is regulated
by ISGylation. We need to evaluate how this gene functions as this is currently an
uncharacterised pathway that could sensitise apoptosis incompetent tumours (most
recurrent cancers). Furthermore, we will evaluate the consequences of expression of MXA in
vivo – and assess its effects on tumour progression. This will deliver valuable insights into the
molecular mechanisms regulating cell viability in cancer cells and a new understanding of
how it may be manipulated for therapeutic purposes.
