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Proline ‐ A Critical “Stress Substrate” for Bioenergetics and Programmed Cell Death
Author(s) -
Phang James Ming,
Pandhare Jui,
Borchert Greg,
Donald Steven P.,
Liu Yongmin
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.794.2
Subject(s) - proline , downregulation and upregulation , proline dehydrogenase , bioenergetics , microbiology and biotechnology , apoptosis , programmed cell death , chemistry , oxidative stress , biochemistry , biology , cancer research , mitochondrion , amino acid , gene
Cancer can use “stress substrates” for survival or apoptosis. A “stress substrate” must be readily available and its metabolism responsive to stress challenges. Proline is abundant in collagen, and collagen makes up 25% of total body protein. Importantly, matrix metalloproteinases (MMP) degrading ECM collagen are upregulated during tumor invasion, chronic inflammation and starvation. Thus, proline satisfies the first criterion for a stress substrate. Secondly, we showed that proline oxidase (POX) a.k.a. proline dehydrogenase, the first enzyme in proline degradation, is upregulated by genotoxic stress (p53), inflammatory stress (PPARγ and its ligands), and nutrient stress (AICAR and Rapamycin). POX is an FAD‐dependent enzyme tightly bound to mitochondrial inner membranes. Electrons from proline can be used to generate ATP or they can reduce oxygen to superoxide. The former is used for bioenergetic maintenance under nutrient stress, and the latter can be a mechanism inducing both intrinsic and extrinsic mechanisms for apoptosis. Relevant to cancer, the apoptotic effects of PPARγ ligands are markedly inhibited by knockdown of POX by its siRNA, strongly suggesting that the upregulation of POX may play a critical role in PPARγ‐dependent anticancer effects. Thus, the metabolism of proline as a critical “stress substrate” is a potential target for the prevention and treatment of cancer.