Cyclic AMP modulation and its effects on chemo-resistant colon cancer cell proliferation and survival

McEwan, David G (2008) Cyclic AMP modulation and its effects on chemo-resistant colon cancer cell proliferation and survival. PhD thesis, University of Glasgow.

Abstract

One of the major problems associated with colorectal cancer is resistance to cytotoxic chemotherapeutic agents. New strategies are therefore required to inhibit colon cancer proliferation and survival. Here I use modulators of cAMP pathways, including inhibitors of phosphodiesterase 4 (PDE4) enzymes, which are under clinical development for other disease states, to inhibit the breakdown of cAMP and to assess the effects of raising intracellular cAMP on colon cancer proliferation and survival. I found that some chemo-resistant cancer cells are addicted to keeping low cAMP in PDE4 regulated compartments, and modulation of this pool causes G1/S-phase arrest and apoptosis. I also show that PDE4 controlled cAMP negatively regulates the PI 3-Kinase/Akt pathway, which some cells are addicted to for survival. Furthermore, I investigated the expression and role of PDE4 enzymes in metastatic colon cancer cells and assessed the effects of modulating their expression on survival. Also, I used a clinically relevant analogue of forskolin, an agonist of adenylyl cyclase, to examine the general effect on growth of epithelial cancer cell lines. This work might provide new strategies for the treatment of advanced colon cancer.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: cyclic AMP, cAMP, phosphodiesterases, PDE, PDE4, colorectal cancer, Chemo-resistance, PI 3-kinase, Akt, oncogene, addiction, proliferation, apoptosis
• Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Supervisor's Name: Frame, Professor Margaret C and Houslay, Professor Miles D
• Date of Award: 2008
• Depositing User: Dr David G McEwan
• Unique ID: glathesis:2008-81
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 10 Mar 2008
• Last Modified: 10 Dec 2012 13:15
• URI: https://theses.gla.ac.uk/id/eprint/81