Collagen metabolism as a regulator of proline dehydrogenase/proline oxidase-dependent apoptosis/autophagy

Abstract

Recent studies on the regulatory role of amino acids in cell metabolism have focused on the functional significance of proline degradation. The process is catalysed by proline dehydrogenase/proline oxidase (PRODH/POX), a mitochondrial flavin-dependent enzyme converting proline into ∆1-pyrroline-5-carboxylate (P5C). During this process, electrons are transferred to electron transport chain producing ATP for survival or they directly reduce oxygen, producing reactive oxygen species (ROS) inducing apoptosis/autophagy. However, the mechanism for switching survival/apoptosis mode is unknown. Although PRODH/POX activity and energetic metabolism were suggested as an underlying mechanism for the survival/apoptosis switch, proline availability for this enzyme is also important. Proline availability is regulated by prolidase (proline supporting enzyme), collagen biosynthesis (proline utilizing process) and proline synthesis from glutamine, glutamate, α-ketoglutarate (α-KG) and ornithine. Proline availability is dependent on the rate of glycolysis, TCA and urea cycles, proline metabolism, collagen biosynthesis and its degradation. It is well established that proline synthesis enzymes, P5C synthetase and P5C reductase as well as collagen prolyl hydroxylases are up-regulated in most of cancer types and control rates of collagen biosynthesis. Up-regulation of collagen prolyl hydroxylase and its exhaustion of ascorbate and α-KG may compete with DNA and histone demethylases (that require the same cofactors) to influence metabolic epigenetics. This knowledge led us to hypothesize that up-regulation of prolidase and PRODH/POX with inhibition of collagen biosynthesis may represent potential pharmacotherapeutic approach to induce apoptosis or autophagic death in cancer cells. These aspects of proline metabolism are discussed in the review as an approach to understand complex regulatory mechanisms driving PRODH/POX-dependent apoptosis/survival.

PRODH/POX-Dependent Celecoxib-Induced Apoptosis in MCF-7 Breast Cancer

“…We found that, in MCF-7 shPRODH/POX clones, the generation of NAD+/NADH and NADP+/NADPH was decreased in comparison to MCF-7 cells carrying PRODH/POX. NADP+ and NADPH are necessary when P5C is reduced to proline [ 29 ]. The reduction in NAD+/NADH and NADP+/NADPH levels reduces the availability of nucleotides for DNA biosynthesis and, as result, cell proliferation [ 30 ].…”

Free Amino Acid Alterations in Patients with Gynecological and Breast Cancer: A Review

“…Currently, numerous teams have demonstrated that proline is involved in many biochemical processes playing a significant role as an osmoprotectant, metal chelator, protein chaperone, ROS scavenger, energy source, a regulator of redox balance and NADP+/NADPH level in the cytosol, as well as a signaling molecule in apoptosis/autophagy [ 127 ]. Proline metabolism has also been implicated as a metabolic pathway impacted on DNA biosynthesis and epigenetic modifications [ 129 ]. Proline synthesis, degradation, and cycling are dysregulated in the microenvironment of cancer cells leading to the impairment of cell proliferation, survival, metastasis, and extracellular matrix function.…”

“…P5C dehydrogenase (P5CDH) using nicotinamide adenine dinucleotide converts GSA to glutamate that can enter the TCA cycle as an α-ketoglutarate. Proline is also converted by OAT into ornithine, a component of the urea cycle [ 129 ]. Moreover, proline can be incorporated into collagen molecule, which is a reservoir for proline, since approximately 25% of all its residues constitute prolyl or hydroxyprolyl groups [ 132 ].…”

“…At the biochemical level, a possible explanation for increased intracellular proline concentration could be the activation of metalloproteinases (MMPs), mainly MMP-2 and -9, causing collagen degradation. Increased collagen breakdown results in (1) increased cancer cell metastatic potential through enhanced mobility and (2) intensive proline release as an alternative energy source [ 129 ]. Under conditions of nutrient depletion or hypoxia, proline may serve as an energy source in the microenvironment of cancer cells.…”

“…It demands a remarkable quantity of building blocks for protein and DNA synthesis. Therefore, cancer cell reprograms its function to decrease the rate of collagen biosynthesis and make proline available for PRODH/POX activity [ 129 ]. Proline can fuel the production of macromolecules through upregulation of oncogenic factor c-MYC [ 136 ] and PI3K [ 137 ] signaling pathways.…”