The signal transduction network encompassing the lipid kinase, phosphoinositide-3-kinase (PI3K) is perhaps the most commonly corrupted signaling network in human cancers. PI3K produces the lipid second messenger phosphatidylinositol-3,4,5-triphosphate (PIP3) which recruits effector proteins, such as the kinase Akt, to the membrane where they can be activated. Under physiological conditions PI3K is activated by secreted ligands such as hormones, cytokines, and growth factors that serve to relay the systemic nutrient status of the organism. In cancer PI3K signaling becomes growth factor-independent due either to its own mutations (mutations in the PIK3CA gene are the second most common in cancer) or mutations in the major oncoproteins and tumor suppressors that lie upstream (e.g. EGFR, MET, Ras, PTEN). One of the major functions of PI3K is to coordinate nutrient uptake with cellular metabolism and macromolecule biosynthesis. However, there is a surprisingly short list of post-translational control points through which PI3K is known to control metabolic activity. Few metabolites play a more central role in metabolism than Coenzyme A (CoA). CoA shuttles carbon within the cell (as acetyl-CoA for instance) and is essential for several core metabolic processes including the TCA cycle and de novo lipid synthesis. In the mitochondria, CoA accepts carbon from glycolysis-derived pyruvate to form acetyl-CoA and initiate the TCA cycle. In the cytosol, citrate from the mitochondria is used by ATP citrate lyase (ACLY) to form acetyl-CoA. This cytosolic acetyl-CoA is used as a carbon donor for de novo lipid synthesis, among other important roles. Interestingly, ACLY has been shown to be important for tumorigenesis as its knock down inhibits tumor growth. CoA is synthesized from Vitamin B5 (also known as pantothenate), cysteine, and an ADP moiety from ATP in a highly conserved five step metabolic pathway. Vitamin B5 is uniquely utilized in the CoA synthesis pathway and is an essential nutrient that must be taken up in the diet of higher organisms. The rate-limiting step of CoA biosynthesis is catalyzed by pantothenate kinase (PANK) which has four isoforms from separate genes in vertebrates. Unlike for acetyl- CoA, the requirement for de novo synthesis of CoA in tumors has not been explored. Preliminary data suggests that non-dividing cells may have stable pools of CoA and much lower requirements for its de novo synthesis than proliferating cells. Using a metabolomics approach, I have recently discovered a link between PI3K signaling and the de novo synthesis of CoA. Signals emanating from PI3K acutely increase metabolite levels in this pathway and at the same time increase phosphorylation of the PANK enzymes which catalyze the pathway's rate limiting step. My goal is to understand the role of PI3K in regulating CoA, and the role of CoA in supporting the PI3K-dependent metabolic program that is so intensely selected for in tumors. Dependencies within this relationship may be therapeutically exploited. During the K99 phase I will identify the molecular mechanism by which PI3K signaling stimulates CoA synthesis and begin to determine the requirements for CoA in cellular growth and survival. During the K00 phase I will determine the effects of oncogenic PI3K signaling on CoA synthesis in tumors and evaluate the therapeutic potential of blocking CoA synthesis for the treatment of oncogenic PI3K-driven breast cancer. This study will establish a new branch of PI3K signaling and expand our understanding of the metabolic dependencies of PI3K-dependent cancers. The mentored phase of this award will be completed at Beth Israel Deaconess Medical Center and Harvard Medical School under the guidance of Dr. Alex Toker, an expert in molecular signaling mechanisms and breast cancer biology, and in collaboration with Dr. John Asara, a bioanalytical chemist and pioneer in the field of cellular metabolomics. This inspiring and supportive research environment is an ideal training ground for an aspiring independent scientist.
The PI3K signaling pathway is a major regulator of cellular metabolism and growth, and is perhaps the most frequently corrupted pathway in human cancer. Our understanding of how PI3K coordinates metabolism is incomplete and so this research examines the regulatory relationship between PI3K signaling and one of the most central facilitators of metabolic activity, Coenzyme A. Results of this study will provide insights into why this pathway is so important for tumor formation and may suggest new targeted therapies to treat cancer.
|Toker, Alex; Dibble, Christian C (2018) PI 3-Kinase Signaling: AKTing up inside the Cell. Mol Cell 71:875-876|