The role of phosphoenolpyruvate carboxykinase (PCK) in breast cancer.

Klaver, L. (Lotje) (2014) The role of phosphoenolpyruvate carboxykinase (PCK) in breast cancer. thesis, Medicine.

Text KlaverC.pdf Restricted to Registered users only Download (3MB)

Abstract

Background: In the last decade, research in the field of cancer cell metabolism has contributed to progressive insight in cancer biology. Cancer cells reprogram cell metabolism in order to produce a sufficient amount of precursors required for proliferation. Moreover, extreme tumour microenvironments require major adaptations in metabolism. Phosphoenolpyruvate carboxykinase (PCK) is an enzyme at the intersection of two key metabolic pathways (namely the glycolytic pathway and the TCA-cycle) and therefore could provide cells with high metabolic flexibility. Aim: Investigation of the expression and function of PCK in cancer. This could expand current knowledge of cancer cell metabolism and contribute to the development of therapeutic approaches. Results: The mitochondrial isoform, PCK2, is expressed in primary human breast cancer. PCK2 is induced in both MCF-7 and MDA-231 breast cancer cells after exposure to severe hypoxia and glutamine deprivation. In both conditions, also ATF4 expression is increased. ATF4 coordinates the integrated stress response, a stress responsive pathway associated with poor prognosis and therapeutic resistance. In ATF4 depletion, PCK2 expression is considerably reduced, indicating that ATF4 regulates PCK2. Furthermore, if only lactate is available PCK2 is induced in MCF-7 cells, indicating a role for PCK2 in lactate utilisation. Serine depletion does not induce PCK2 expression in MCF-7 and MDA-231 cell lines. Discussion and conclusion: PCK2 might have a function as part of the integrated stress response. PCK2 could maintain TCA-cycle flux in conditions were flux is threatened, by regulating cata- and anaplerosis. Moreover, PCK2 might enable proliferating cells to use lactate carbons for biosynthesis when other nutrients are not available. Finally, PCK2 could provide the glycolytic intermediate 3PG for serine synthesis in breast cancer cells dependent on high serine pathway flux. In short, PCK2 might play an interesting role in breast cancer cell metabolism and further investigation will focus on confirming our hypotheses. Methods: Results in this study were obtained using quantitative real time PCR, Western blotting, immunofluorescence and CyQuant survival and proliferation assays.

Item Type:	Thesis (Thesis)
Supervisor name:	Vries, Prof. Dr. E.G.E. de and Kallenberg, Prof. Dr. C.G.M.
Supervisor name:	Harris, Prof. Dr. A.L. and Favaro, Dr. E. and University of Oxford
Faculty:	Medical Sciences
Date Deposited:	25 Jun 2020 11:01
Last Modified:	25 Jun 2020 11:01
URI:	https://umcg.studenttheses.ub.rug.nl/id/eprint/2154

Actions (login required)

View Item