[Frontiers in Bioscience 17, 1835-1845, January 1, 2012]

Proline metabolism and cancer

James M. Phang1, Wei Liu1

1Metabolism and Cancer Susceptibility Section, Laboratory of Comparative Carcinogenesis, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA

TABLE OF CONTENTS

1. Abstract
2. Introduction
2.1. Proline cycle
2.2. P5C reductase
2.3. Proline oxidase
2.4. Tumor microenvironment
3. POX as metabolic tumor suppressor
3.1. Mechanisms characterized in tissue culture
3.2. POX suppresses tumors in xenograft tumors
3.3. POX is downregulated in human tumors
4. Mechanism for POX downregulation in tumors
4.1. Identification of miR-23b*
4.2. POX and miR-23b* in human clear cell renal carcinomas
4.3. Reversal of POX suppression by inhibiting miR-23b*
5. Other mechanisms for inducing POX
5.1. PPARgamma
5.2. Physiologic ligand for PPARgamma upregulates POX
5.3. PPARgamma and autophagy
6. Autophagy and survival
6.1. POX and nutrient deprivation in autophagy
6.2. Proline and glutamine
6.3. Proline and hydroxyproline in anaplerosis
7. Metabolism in the tumor microenvironment
7.1. Glucose and glutamine in tissue culture
7.2. Degradation of extracellular matrix by MMPs
7.3. MMPs and tumorigenesis
8. Metabolic time line in tumorigenesis
9. Perspective
10. Acknowledgements
11. References

1. ABSTRACT

Proline plays a special role in cancer metabolism. Proline oxidase (POX), a.k.a. proline dehydrogenase (PRODH), is among a few genes induced rapidly and robustly by P53, the tumor suppressor. Ectopic expression of POX under control of tet-off promoter initiated mitochondrial apoptosis. The mechanism activated by POX is mediated by its production of ROS. In immunodeficient mice, POX overexpression markedly retarded growth of xenograft tumors. In human tumors of the digestive tract and kidney, POX was markedly decreased, suggesting that the suppressive effect of POX was downregulated. This was not due to POX gene mutations or hypermethylation. Instead, a microRNA, miR-23b*, expressed at high levels in tumors, was a potent inhibitor of POX expression. Furthermore, antagomirs of miR-23b* reversed the downregulated expression of POX and its tumor-suppressive effect, thereby providing a therapeutic strategy. POX not only responds to genotoxic stress, but also to inflammatory and metabolic stress. Depending on microenvironmental and temporal factors, POX can mediate oppositely-directed responses-programmed cell death, on the one hand, and survival, on the other.