ALDH3A1 Expression Is Modulated by Docosahexaenoic Acid through Peroxisome Proliferator-Activated Receptors (PPARs) in Human Lung Adenocarcinoma Cells

Aliphatic aldehydes derived from the peroxidation of polyunsaturated fatty acids (PUFAs) are highly reactive compounds known to modulate several cell functions, and their intracellular accumulation is inversely related to the proliferation rate. In proliferating tumor cells, the low level of cytostatic aldehydes is also due to the increased expression of cytosolic class 3 aldehyde dehydrogenase (ALDH3). In fact, ALDH3 inhibition by inhibitors or antisense oligonucleotides decreases cell proliferation in tumor cells. ALDH3 activity and tumor cell proliferation are also reduced by some peroxisome proliferators, such as arachidonic acid, belonging to ω-6 PUFAs, via modulation of peroxisome proliferator-activated receptors (PPARs). In arachidonic acid-treated cells the observed effects are mediated by decreased DNA-binding activity of NFkB. Since it is well known that ω-6 and ω-3 PUFAs can show opposite effect, we here investigated the effect of docosahexaenoic acid, an ω-3 PUFAs on ALDH3A1 in human A549 lung cancer cells, in order to verify whether both types of PUFAs affect ALDH3A1 expression in the same way. In particular, the signal transduction pathways responsible for the ALDH3A1 modulation after docosahexaenoic acid exposure were examined. The results show that, like arachidonic acid, docosahexaenoic acid inhibits both ALDH3 expression and tumor cell growth, and that the effect is mediated by the induction of PPARs and lipid peroxidation, and the by the decrease of both AP-1 and NFkB DNAbinding activity. This decrease may, in turn, reduce the transcription of the ALDH3 gene, which contains in its promoter consensus sequences for both transcription factors. The importance of lipid peroxidation induction in determining docosahexaenoic acid effect is confirmed by the observation that anti-oxidant treatment completely prevents all the observed effects. The most important conclusion arising from the results in A549 cells treated with docosahexaenoic acid is that tumor cell growth can be reduced by modulating ALDH3 and that this important goal can be achieved using natural substances such as ω-3 PUFAs. Moreover, this observation can also help to explain the mechanisms underlying the anti-tumor properties ascribed to this PUFA family. This type of approach could be especially useful in inhibiting growth of tumor cells characterized by increased expression of ALDH3.