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Fatty acid oxidation and signaling in apoptosis
Dean G Tang1, Eunhye La, Julie Kern
1Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas, Austin 78712, USA.
Abstract:
It is well established that fatty acid metabolites of cyclooxygenase, lipoxygenase (LOX), and cytochrome P450 are implicated in essential aspects of cellular signaling including the induction of programmed cell death. Here we review the roles of enzymatic and non-enzymatic products of polyunsaturated fatty acids in controlling cell growth and apoptosis. Also, the spontaneous oxidation of polyunsaturated fatty acids yields reactive aldehydes and other products of lipid peroxidation that are potentially toxic to cells and may also signal apoptosis. Significant conflicting data in terms of the role of LOX enzymes are highlighted, prompting a re-evaluation of the relationship between LOX and prostate cancer cell survival. We include new data showing that LNCaP, PC3, and Du145 cells express much lower levels of 5-LOX mRNA and protein compared with normal prostate epithelial cells (NHP2) and primary prostate carcinoma cells (TP1). Although the 5-LOX activating protein inhibitor MK886 killed these cells, another 5-LOX inhibitor AA861 hardly showed any effect. These observations suggest that 5-LOX is unlikely to be a prostate cancer cell survival factor, implying that the mechanisms by which LOX inhibitors induce apoptosis are more complex than expected. This review also suggests several mechanisms involving peroxisome proliferator activated receptor activation, BCL proteins, thiol regulation, and mitochondrial and kinase signaling by which cell death may be produced in response to changes in non-esterified and non-protein bound fatty acid levels. Overall, this review provides a context within which the effects of fatty acids and fatty acid oxidation products on signal transduction pathways, particularly those involved in apoptosis, can be considered in terms of their overall importance relative to the much better studied protein or peptide signaling factors.
Insights
Fatty acid oxidation products influence cell death, but lipoxygenase (LOX) may not promote prostate cancer survival. Further research is needed to understand LOX inhibitor mechanisms in apoptosis.
Area of Science:
- Biochemistry
- Cell Biology
- Oncology
Background:
- Fatty acid metabolites from cyclooxygenase, lipoxygenase (LOX), and cytochrome P450 are involved in cellular signaling and programmed cell death.
- Polyunsaturated fatty acids (PUFAs) and their oxidation products, including lipid peroxidation products, play roles in cell growth and apoptosis.
- Conflicting data exists regarding the role of LOX enzymes in cancer, particularly prostate cancer.
Purpose of the Study:
- To review the roles of enzymatic and non-enzymatic products of PUFAs in controlling cell growth and apoptosis.
- To re-evaluate the relationship between LOX and prostate cancer cell survival.
- To present new data on 5-LOX expression in prostate cancer cells and the effects of inhibitors.
Main Methods:
- Literature review of fatty acid metabolism and apoptosis signaling.
- Analysis of mRNA and protein expression of 5-lipoxygenase (5-LOX) in prostate cancer cell lines (LNCaP, PC3, Du145) and normal prostate epithelial cells (NHP2).
- Inhibition studies using 5-LOX inhibitors (MK886, AA861) to assess effects on prostate cancer cell viability.
Main Results:
- Prostate cancer cell lines (LNCaP, PC3, Du145) showed significantly lower 5-LOX mRNA and protein levels compared to normal prostate epithelial cells (NHP2).
- The 5-LOX inhibitor MK886 induced apoptosis in these cells, while AA861 had minimal effect.
- These findings challenge the notion that 5-LOX is a critical survival factor in prostate cancer.
Conclusions:
- The mechanisms by which LOX inhibitors induce apoptosis in prostate cancer cells are complex and not solely dependent on 5-LOX activity.
- Other signaling pathways, including peroxisome proliferator-activated receptor (PPAR) activation, BCL proteins, thiol regulation, and mitochondrial/kinase signaling, are likely involved in fatty acid-mediated apoptosis.
- Fatty acids and their oxidation products represent an important, yet understudied, class of signaling factors in apoptosis, comparable to protein and peptide signaling molecules.