Proline Metabolism in Cell Regulation and Cancer Biology: Recent Advances and Hypotheses

Abstract

Significance: It is increasingly clear that proline metabolism plays an important role in metabolic reprogramming, not only in cancer but also in related fields such as aging, senescence, and development. Although first focused on proline catabolism, recent studies from a number of laboratories have emphasized the regulatory effects of proline synthesis and proline cycling. Recent Advances: Although proline dehydrogenase/proline oxidase (PRODH/POX) has been known as a tumor protein 53 (P53)-activated source of redox signaling for initiating apoptosis and autophagy, senescence has been added to the responses. On the biosynthetic side, two well-recognized oncogenes, c-MYC and phosphoinositide 3-kinase (PI3K), markedly upregulate enzymes of proline synthesis; mechanisms affected include augmented redox cycling and maintenance of pyridine nucleotides. The reprogramming has been shown to shift in clonogenesis and/or metastasis.

Critical issues: Although PRODH/POX generates reactive oxygen species (ROS) for signaling, the cellular endpoint is variable and dependent on metabolic context; the switches for these responses remain unknown. On the synthetic side, the enzymes require more complete characterization in various cancers, and demonstration of coupling of proline metabolites to other pathways may require studies of protein-protein interactions, membrane transporters, and shuttles.

Future directions: The proline metabolic axis can serve as a scaffold on which a variety of regulatory mechanisms are integrated. Once understood as a central mechanism in cancer metabolism, proline metabolism may be a good target for adjunctive cancer therapy.

Keywords: metastasis; proline cycle; pyridine nucleotides; redox signaling; resistance to oxidative stress; senescence.

FIG. 1.

Proline metabolic pathway. 1, pyrroline-5-carboxylate reductase; 2, proline dehydrogenase/proline oxidase; 3, pyrroline-5-carboxylate synthase; 4, spontaneous; 5, glutamate dehydrogenase; 6, glutaminase; 7, ornithine aminotransferase, 8, ornithine transcarbamylase; 9, arginase, 10, ornithine decarboxylase, 11, nitric oxide synthase; 12, pyrroline-5-carboxylate dehydrogenase. α-KG, α-ketoglutarate; ARG, arginine; CIT, citrulline; CP, carbamoyl phosphate; GLN, glutamine; GLU, glutamate; GSA, glutamic-γ-semialdehyde; NO, nitric oxide; ORN, ornithine; P5C, Δ¹-pyrroline-5-carboxylate; PRO, proline; PUT, putrescine; enzymes; TCA, tricarboxylic acid.

FIG. 2.

PRODH/POX-mediated signaling. AMPK, AMP-activated protein kinase; ETC, electron transport chain; MYC, myelocytomatosis oncogene cellular homologue; PPARγ, peroxisome proliferator-activated receptor gamma. PRODH/POX, proline dehydrogenase/proline oxidase; ROS, reactive oxygen species.

FIG. 3.

Hypothesis for proline cycle revised. The cycle has been revised according to locations of the enzymes. The colored areas are for emphasis and do not represent specific locations. The dotted arrows represent putative shuttle systems, for example, malate/aspartate shuttle. PYCR1/2/L, pyrroline-5-carboxylate reductase 1/2/L.

FIG. 4.

Recently described regulation based on proline metabolic axis. References: “Extended lifespan” (106); “Innate immunity” (91); “Adipocyte stress resistance” (44); “Stem cell behavior” (11); “Autophagy neuronal cell” (69). Duox, dual oxidase; esMT, embryonic stem cell-to-mesenchyme-like transition (for details see text); HIV, human immunodeficiency virus; IGF, insulin-like growth factor.

FIG. 5.

Pathways activated by MYC and PI3K. Enzymes or pathways upregulated by MYC and PI3K are shown in red. Abbreviations are as shown in figures 1–3. NAD, total nicotinamide adenine dinucleotide; NADP, total nicotinamide adenine dinucleotide phosphate; NAM, nicotinamide; NAMPT, nicotinamide phosphoryl transferase; NMN, nicotinamide mononucleotide; OxPPP, oxidative arm of pentose phosphate pathway; PRPP, phosphoribosyl pyrophosphate; R-5-P, ribose-5-phosphate; SIRT1, sirtuin 1.

FIG. 6.

Regulation of the oxidative arm of the pentose phosphate pathway, adapted from Jiang et al. (34). AMPK, AMP-activated protein kinase; ATM, ataxia telangiectasia mutated protein kinase; mTORC1, mammalian target of rapamycin1; MYC, myelocytomatosis oncogene cellular homologue; PI3K, phosphoinositide 3 kinase; PTEN, phosphatase and tensin homologue.

FIG. 7.

Protein–protein interactions with PYCR. References: DJ-1 (100); ORAOV1 (92); RRM2B (39). DJ-1, protein deglycase; ORAOV1, oral cancer overexpressed 1; PARK-7, Parkinson's disease protein 7; RRM2B, ribonucleoside-diphosphate reductase subunit M2B.