Microtubules and Energy Metabolism: Targets for Standard, Combination, and Novel Therapeutic Interventions and Monitoring of Cancer

• Author / Creator

  Friesen, Douglas E

• The challenge of understanding and treating cancer has proven to be exceedingly complex. At this juncture, understanding cancer from the perspective of a breakdown of a complex cooperative system using a biophysical analysis may aid in improved treatments and prevention of this disease. In any system, the following are crucial: the right raw materials and energy, the right vision and instructions, solid communication, and the right framework to hold everything together. In the biological system of an organism, these aspects roughly correspond to the right nutrition to fuel the organism, the proper genome to create the right proteins to create the organism, solid inter- and intra-cellular communication, and a robust structure involving the cytoskeleton of a cell and the extracellular matrix that keeps the organism ordered and stable. This thesis explores in depth the ideas of communication, structure, and energy, which are all crucial for a multicellular system to operate. My goal is that by providing insight into these aspects of an organism’s optimal function, improved treatments for cancer may be developed. The cytoskeleton of a cell is the component that provides the structure that the cell requires to maintain its shape under external forces. I explore in the most depth the properties of microtubules, which form the most rigid component of the cytoskeleton, that may be involved in intracellular electrical communication in addition to their more familiar structural role. Initially, I studied gamma-tubulin, which is a protein that forms a nucleating ring that nucleates microtubules. Using molecular dynamics simulations, I investigated the binding site of what were, to my knowledge, the first inhibitors found to interact with gamma-tubulin. This study could lead to more potent inhibitors of gamma-tubulin, which will allow for a more detailed exploration of the role gamma-tubulin plays in maintaining the structure of the cell, and provide a possible chemotherapeutic target for glioblastoma multiforme, a form of brain cancer with one of the poorest prognoses of all human cancers where gamma-tubulin is upregulated. Next, I investigated the role of energy metabolism in cancer, which may play a crucial role in maintaining the proper structure of the cytoskeleton. This investigation led to the possibility of improving our understanding of the cause of cachexia in late stage cancer patients, where these patients experience muscle wasting that is not able to be corrected through nutritional support. I present a mathematical framework for evaluating how an altered energy metabolism seen in cancer cells can help explain this muscle wasting that cancer patients experience. This model, if validated, could lead to improved treatment for cancer patients experiencing cachexia. I also evaluate the potential of the drug 3-bromopyruvate, which targets the altered energy metabolism in cancer cells, as a combination drug treatment for recurrent epithelial ovarian cancer. I initiated a study finding that 3-bromopyruvate is more cytotoxic to late stage ovarian cancer over early-stage ovarian cancer in a cell line progression model, which supports progressing to in vivo testing of the drug in a mouse model. Finally, I explore the role of microtubules in the cell for intracellular electrical signaling. Microtubules have been hypothesized to be a component of an organism-wide electrical signaling network in the body, and I developed a microfabricated device to test electrical properties of microtubules in a physiological-like ionic solution. My preliminary results support the idea that microtubules are able to increase ionic conductivity, and provide an experimental system to facilitate testing microtubules’ electrical effects in greater detail. As a result of the work presented in this thesis, I have added insight into microtubules’ role in electrical intracellular communication and how gamma-tubulin may be inhibited to understand its function in the cell more completely. I have also brought insight into how energy metabolism can both help explain cancer cachexia and be targeted for improved ovarian cancer therapy. These insights provide a greater framework for understanding cancer, through ideas of energy, electrical communication, and structure. I trust these insights will help the development of standard, combination, and novel treatments of cancer, as well as preventative measures to maintain an organism’s order, structure, and proper energy metabolism.

• Subjects / Keywords

  • Cancer
  • Energy metabolism
  • Cachexia
  • Mitochondria
  • Microtubules
  • Conductivity

• Graduation date

  Spring 2016

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R3M03ZC22

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.