Proline dehydrogenase (oxidase) in cancer

Abstract

Proline dehydrogenase (oxidase, PRODH/POX), the first enzyme in the proline degradative pathway, plays a special role in tumorigenesis and tumor development. Proline metabolism catalyzed by PRODH/POX is closely linked with the tricarboxylic acid (TCA) cycle and urea cycle. The proline cycle formed by the interconversion of proline and Δ(1) -pyrroline-5-carboxylate (P5C) between mitochondria and cytosol interlocks with pentose phosphate pathway. Importantly, by catalyzing proline to P5C, PRODH/POX donates electrons into the electron transport chain to generate ROS or ATP. In earlier studies, we found that PRODH/POX functions as a tumor suppressor to initiate apoptosis, inhibit tumor growth, and block the cell cycle, all by ROS signaling. It also suppresses hypoxia inducible factor signaling by increasing α-ketoglutarate. During tumor progression, PRODH/POX is under the control of various tumor-associated factors, such as tumor suppressor p53, inflammatory factor peroxisome proliferator-activated receptor gamma (PPARγ), onco-miRNA miR-23b*, and oncogenic transcription factor c-MYC. Recent studies revealed the two-sided features of PRODH/POX-mediated regulation. Under metabolic stress such as oxygen and glucose deprivation, PRODH/POX can be induced to serve as a tumor survival factor through ATP production or ROS-induced autophagy. The paradoxical roles of PRODH/POX can be understood considering the temporal and spatial context of the tumor. Further studies will provide additional insights into this protein and on its metabolic effects in tumors, which may lead to new therapeutic strategies.

Functional Consequences of Intracellular Proline Levels Manipulation Affecting PRODH/POX–Dependent Pro-Apoptotic Pathways in a Novel in Vitro Cell Culture Model

“…Although the functional significance of proline catabolism by PRODH/POX is well recognized [13, 15, 23, 24] the mechanism of PRODH/POX-dependent apoptosis and autophagy is poorly understood. Here we provide evidence that PRODH/POX silencing contributes to induction of pro-survival pathways in MCF-7 cells.…”

“…On the other hand, P5C is converted in cytoplasm to proline by P5C reductase. The interconversion is known as a “proline cycle” (conversion of proline-P5C in mitochondria by PRODH/POX and P5C-proline in cytosol by P5C-reductase) that transfers reducing and oxidizing potential between mitochondria and cytosol using NAPDH/NADP + [23, 24]. This shuttle is coupled to glycolisys and pentose phosphate pathway that supports biosynthesis of pyridine nucleotides [10] .…”

“…mTOR pathway is dependent on the availability of nutrients [24, 42]. Inhibition of mTOR by Rap and/or by glucose deprivation upregulates PRODH/POX expression [13, 24, 29].…”

“…Proline and its metabolism play an important role in the proper functioning of the cell [4]. Proline is known to act as a stress signalling molecule in mitochondria [11, 22, 25] and cytoplasm [4, 7, 23, 24]. Proline bearing reducing potential must be converted in mitochondria to P5C by PRODH/POX for regeneration of oxidizing potential.…”

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

“…Separate from transamination reactions, carbon and nitrogen from glutamate can be used to produce proline, which plays a key role in the production of the extracellular matrix protein collagen 80 (Figure 3). While proline can be degraded to glutamate 81 , the MYC oncoprotein can alter the expression of proline synthesis and degradation enzymes to promote the net synthesis of proline from glutamine-derived glutamate 82 . Overall, tracer experiments determined that at least 50% of non-essential amino acids used in protein synthesis by cancer cells in vitro can be directly derived from glutamine 16,83 .…”