The proline regulatory axis and cancer

Abstract

Studies in metabolism and cancer have characterized changes in core pathways involving glucose and glutamine, emphasizing the provision of substrates for building cell mass. But recent findings suggest that pathways previously considered peripheral may play a critical role providing mechanisms for cell regulation. Several of these mechanisms involve the metabolism of non-essential amino acids, for example, the channeling of glycolytic intermediates into the serine pathway for one-carbon transfers. Historically, we proposed that the proline biosynthetic pathway participated in a metabolic interlock with glucose metabolism. The discovery that proline degradation is activated by p53 directed our attention to the initiation of apoptosis by proline oxidase/dehydrogenase. Now, however, we find that the biosynthetic mechanisms and the metabolic interlock may depend on the pathway from glutamine to proline, and it is markedly activated by the oncogene MYC. These findings add a new dimension to the proline regulatory axis in cancer and present attractive potential targets for cancer treatment.

Keywords: MYC oncogene; glutamine metabolism; proline metabolism; redox regulation; tumor suppressor function.

Figure 1

Schematic of proposed parametabolic regulation. The A-B pathway is in a metabolic interlock with the S-M pathway. Genetic or epigenetic upregulation of the A-B pathway would result in an increased production of P. The designated symbols are generic. However, in the context of the proline regulatory axis, A-B would represent the glutamine to proline pathway, I₁, and I₂ would be pyridine nucleotides, the S-M pathway would represent the oxidative arm of the pentose phosphate pathway and P would be PP-ribose-P. “Exit” may be either excretion, incorporation into protein, or another mechanism for departure from the parametabolic regulatory system.

Figure 2

Structure of molecules in the glutamine-arginine-proline pathway. Glutamic-γ-semialdehyde is the open-chain tautomer of Δ¹-pyrroline-5-carboxylic acid.

Figure 3

Enzymatic pathways in the interconversions of glutamine, arginine, and proline. GSA (glutamic-γ-semialdehyde) and its tautomer, P5C (Δ¹-pyrroline-5-carboxylate) bridge the pathways from glutamine to arginine, thereby linking the TCA and urea cycles. Some reactions are mediated by multiple isozymes with distinct subcellular localizations and functions. The abbreviations are: PRO, proline; HYP, hydroxyproline; GLU, glutamate; GLN, glutamine; a-KG, alphaketoglutarate; ORN, ornithine, CIT, citrulline, ARG, arginine; NO, nitric oxide; PUT, putrescine; CP, carbamyl phosphate. Enzymes catalyzing these reactions are designated by numbers: 1, proline oxidase/dehydrogenase; 2, P5C reductase; 3, P5C synthase; 4, P5C dehydrogenase; 5, glutaminase; 6, ornithine aminotransferases; 7, ornithine transcarbamylase; 8, arginase; 9, ornithine decarboxylase; 10, glutamate dehydrogenase; 11, protein synthesis; 12, prolyl hydroxylase; 13, nitric oxide synthase.

Figure 4

Top: schematic representation of the functions of proline oxidase (POX) in tumor suppression. POX functions as a tumor suppressor even though the gene encoding POX is not a classical tumor suppressor gene. Instead, POX is suppressed by a microRNA, miR-23b* which is over expressed in digestive tract and kidney cancers. For details, see figure in review (Phang and Liu, 2012). Bottom: role of POX signaling under conditions of metabolic stress. The functions of POX depend on metabolic context. Under conditions of glucose or oxygen deprivation or when treated with oxidized LDL, PPARγ, POX expression is upregulated. The proline-dependent ROS generated by POX activate prosurvival autophagy mediated by conversion of LC3 I to LC3 II and by expression of Beclin.

Figure 5

A proposed model for parametabolic redox regulation by the proline regulatory axis. The model is a composite of functions which depend on temporo-spatial context; various activities may not occur simultaneously. For example, MYC inhibits POX but concomitantly activates P5CS and PYCR1 (see text). The enzymes shown are as follows: GLS, glutaminase; GS, glutamine synthase; P5CS, pyrroline-5-carboxylate synthase, P5CDH, pyrroline-5-carboxylate dehydrogenase; POX, proline oxidase/dehydrogenase; PYCR1/2, pyrroline-5-carboxylate reductase 1, and 2; PYCR_L, pyrroline-5-carboxylate reductase L. Some of the pathways are simplified. A single arrow may represent multiple steps.