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Alternol eliminates excessive ATP production by disturbing Krebs cycle in prostate cancer
- Source :
- Prostate
- Publication Year :
- 2019
- Publisher :
- Wiley, 2019.
-
Abstract
- Background Alternol is a natural compound isolated from fermentation products of a mutant fungus. Our previous studies demonstrated that Alternol specifically kills cancer cells but spares benign cells. Methods To investigate the mechanism underlying alternol-induced cancer cell-specific killing effect, we took a comprehensive strategy to identify Alternol's protein targets in prostate cancer cells, including PC-3, C4-2, and 22RV1, plus benign BPH1 cell lines. Major experimental techniques included biotin-streptavidin pulldown assay coupled with mass-spectrometry, in vitro enzyme activity assay for Krebs cycle enzymes and gas chromatography-mass spectrometry (GC-MS) for metabolomic analysis. Results Among 14 verified protein targets, four were Krebs cycle enzymes, fumarate hydratase (FH), malate dehydrogenase-2 (MDH2), dihydrolipoamide acetyltransferase (DLAT) in pyruvate dehydrogenase complex (PDHC) and dihydrolipoamide S-succinyltransferase (DLST) in a-ketoglutarate dehydrogenase complex (KGDHC). Functional assays revealed that PDHC and KGDHC activities at the basal level were significantly higher in prostate cancer cells compared to benign prostate BPH1 cells, while alternol treatment reduced their activities in cancer cells close to the levels in BPH1 cells. Although FH and MDH2 activities were comparable among prostate cancer and benign cell lines at the basal level, Alternol treatment largely increased their activities in cancer cells. Metabolomic analysis revealed that Alternol treatment remarkably reduced the levels of malic acid, fumaric acid, and isocitric acid and mitochondrial respiration in prostate cancer cells. Alternol also drastically reduced mitochondrial respiration and ATP production in PC-3 cells in vitro or in xenograft tissues but not in BPH1 cells or host liver tissues. Conclusions Alternol interacts with multiple Krebs cycle enzymes, resulting in reduced mitochondrial respiration and ATP production in prostate cancer cells and xenograft tissues, providing a novel therapeutic strategy for prostate cancer treatment.
- Subjects :
- Male
0301 basic medicine
Urology
Citric Acid Cycle
Antineoplastic Agents
Apoptosis
Mitochondrion
Heterocyclic Compounds, 4 or More Rings
Article
03 medical and health sciences
Prostate cancer
Adenosine Triphosphate
0302 clinical medicine
Cell Line, Tumor
medicine
Animals
Humans
Cell Proliferation
Chemistry
Prostate
Prostatic Neoplasms
Cancer
Pyruvate dehydrogenase complex
medicine.disease
Mitochondria
Citric acid cycle
030104 developmental biology
Oncology
Biochemistry
Cell culture
030220 oncology & carcinogenesis
Fumarase
Cancer cell
Drug Screening Assays, Antitumor
Subjects
Details
- ISSN :
- 10970045 and 02704137
- Volume :
- 79
- Database :
- OpenAIRE
- Journal :
- The Prostate
- Accession number :
- edsair.doi.dedup.....e75e9f32d53e2a5ff7d4334c4282d383