ACETYL COA CARBOXYLASE 1 IN PROSTATE CANCER AS A CHEMOTHERAPEUTIC TARGET

Deregulation of cellular metabolism has emerged as a hallmark of cancer yet few therapies targeting cellular bioenergetics are utilized in the clinic. A host of cancer types are known depend on de novo fatty acid synthesis to support aberrant proliferation and survival with prostate cancer being a noted example. The data in this dissertation describes the requirement of acetyl-CoA carboxylase 1 (ACC1), the rate-limiting step of de novo fatty acid synthesis, for the development and progression of prostate cancer. Prostate specific deletion of ACC1 activity reduced tumor burden in 12-week-old C57BL/6J mice. However, prostate tumors are able to bypass the requirement for ACC1 by the time mice are 24-weeks of age. Metabolic analysis revealed different prostate cancer cell lines prefer to utilize different sources of fatty acids. Androgen-dependent LNCaP cells tend to metabolize endogenously supplied fatty acids while androgen independent DU145 cells preferentially metabolize exogenously supplied fatty acids. Pharmacological inhibition of ACC by a non-isoform specific inhibitor reduced the ability of each cell line to use their preferred fatty acid source. Interestingly, we also found that pharmacological ACC inhibition also synergizes with paclitaxel in two different taxane-resistant prostate cancer cell lines and co-treatment results in reduced glycolytic and mitochondrial activity. Cumulatively, these data provide the first evidence that ACC1 is required for prostate cancer development and that ACC inhibition can re-sensitize chemoresistant cells to therapy. Further, these studies pose questions concerning potential redundancy between the ACC isoforms and the interplay between diet and therapeutic strategies, both of which must be carefully considered when attempting to inhibit ACC1 for chemotherapeutic purposes.

Grantor dc:publisher

Wake Forest University

Year dc:date.issued

2017

Author dc:creator

• Davis, Amanda

• Acetyl CoA Carboxylase

Language dc:language.iso

en

Handle dc:identifier.uri

http://hdl.handle.net/10339/89866

OAI identifier oai:identifier

oai:wakespace.lib.wfu.edu:10339/89866