Prolidase-proline dehydrogenase/proline oxidase-collagen biosynthesis axis as a potential interface of apoptosis/autophagy

AbstractRecent 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.

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HDAC inhibitors induce proline dehydrogenase (POX) transcription and anti-apoptotic autophagy in triple negative breast cancer

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/gmz097 ◽

2019 ◽

Vol 51 (10) ◽

pp. 1064-1070 ◽

Cited By ~ 3

Author(s):

Huan Fang ◽

Guangshi Du ◽

Qiuju Wu ◽

Rong Liu ◽

Ceshi Chen ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Hdac Inhibitors ◽

Vital Role ◽

Proline Dehydrogenase ◽

Proline Oxidase ◽

Metabolism Pathway ◽

Key Enzyme ◽

Aggressive Subtype

Abstract Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with poor clinical outcomes and without effective targeted therapies. Numerous studies have suggested that HDAC inhibitors (TSA/SAHA) may be effective in TNBCs. Proline oxidase, also known as proline dehydrogenase (POX/PRODH), is a key enzyme in the proline metabolism pathway and plays a vital role in tumorigenesis. In this study, we found that HDAC inhibitors (TSA/SAHA) significantly increased POX expression and autophagy through activating AMPK. Depletion of POX decreased autophagy and increased apoptosis induced by HDAC inhibitors in TNBC cells. These results suggest that POX contributes to cell survival under chemotherapeutic stresses and might serve as a potential target for treatment of TNBC.

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