Pancreatic cancer (PC) is known to be highly resistant to chemotherapy. Transporters, which regulate the influx and efflux of substrates across the plasma membrane, may play a role in PC drug resistance. ABC transporters are a large family of transmembrane proteins with diverse physiological functions, several of which play major roles in cancer drug resistance. Given that 90% of PC express a mutant K-ras oncogene and that PC are highly hypoxic, I postulated that constitutive K-ras activation and/or hypoxia may correlate with ABC transporter expression, which in turn may promote drug resistance in PC. Using normal and PC cell lines either overexpressing mutant K-ras or subjected to hypoxic treatment, mRNA expression was profiled for 48 ABC transporters. My findings indicate that expression of mutant K-ras and hypoxic treatment, as well as long-term exposure to chemotherapy, may contribute to the development of drug resistance in PC cells in part by inducing the expression of ABC transporters.
Similar to ABC transporters, I investigated whether amino acid transporters would mediate drug resistance in PC. The Xc⁻ amino acid transporter (Xc⁻) mediates cellular uptake of cystine for the biosynthesis of glutathione, a major detoxifying agent. Because the Xc⁻ has been regulates the growth of various cancer cell types, and Xc⁻ is expressed in the pancreas, I postulated that the Xc⁻ may be involved in growth and drug resistance in PC. The Xc⁻ transporter is differentially expressed in normal pancreatic tissues and is overexpressed in PC in vivo. Using PC cell lines, I found that cystine uptake via the Xc⁻ was required for growth and survival in response to oxidative stress, and that expression of the Xc⁻ correlated with gemcitabine resistance. Accordingly, inhibition of Xc⁻ expression via siRNA reduced PC cell proliferation and restored sensitivity to gemcitabine. I also identified the anti-inflammatory drug sulfasalazine as a mixed inhibitor of the Xc⁻, which acts to inhibit cell proliferation via reducing Xc⁻ activity and not by reducing NFKB activity. My findings thus indicate that the Xc⁻ plays a role in PC growth in partby contributing to glutathione synthesis to promote PC cell proliferation, survival, and drug resistance.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:BVAU./1627 |
| Date | 05 1900 |
| Creators | Lo, Maisie K.Y. |
| Publisher | University of British Columbia |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | 8377670 bytes, application/pdf |
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