Abstract
DNA damage triggers a network of signaling events that leads to cell cycle arrest or apoptosis. This DNA damage response acts as a mechanism to prevent cancer development. It has been reported that fatty acids (FAs) synthesis is increased in many human tumors while inhibition of fatty acid synthase (FASN) could suppress tumor growth. Here we report that saturated fatty acids (SFAs) play a negative role in DNA damage response. Palmitic acid, as well as stearic acid and myristic acid, compromised the induction of p21 and Bax expression in response to double stranded breaks and ssDNA, while inhibition or knockdown of FASN enhanced these cellular events. SFAs appeared to regulate p21 and Bax expression via Atr-p53 dependent and independent pathways. These effects were only observed in primary mouse embryonic fibroblasts and osteoblasts, but not in immortalized murine NIH3T3, or transformed HCT116 and MCF-7 cell lines. Accordingly, SFAs showed some positive effects on proliferation of MEFs in response to DNA damage. These results suggest that SFAs, by negatively regulating the DNA damage response pathway, might promote cell transformation, and that increased synthesis of SFAs in precancer/cancer cells might contribute to tumor progression and drug resistance.
Highlights
Numerous studies have implicated that fatty acids, fat diet, and obesity play a role in cancer development [1,2,3]
Since DNA damage response plays an important role in preventing tumorigenesis and fatty acids (FAs) synthesis is greatly enhanced in pre-cancer/cancer cells, we attempt to test whether saturated fatty acids (SFAs) affect DNA damage response
We found that palmitic acid itself slightly down-regulated the basal levels of p21 and Bax in mouse embryonic fibroblasts (MEFs) (Fig. 1A), suggesting that palmitic acid can regulate the expression of these molecules via pathways that are not activated by DNA damage
Summary
Numerous studies have implicated that fatty acids, fat diet, and obesity play a role in cancer development [1,2,3]. The concentration of free fatty acids is .500 mM under normal conditions and .1200 mM under fasting, with palmitic acid accounting for 28% [4,5]. They can be obtained from the diet fat or synthesized in the cells, especially in lipogenic tissues such as liver, adipose, and lactating breast. For people with a balanced diet, de novo fatty acid synthesis is insignificant and FASN protein level is very low in lipogenic as well as other tissues. FAs play important roles in energy storage, membrane structure, protein acylation, signal transduction, and regulation of gene transcription [6]
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