saturated fatty acids modulate cell response to dna damage implication for their role in tumorigenesis饱和脂肪酸调节细胞dna损伤反应的含义在肿瘤发生中的作用.pdfVIP

Saturated Fatty Acids Modulate Cell Response to DNA Damage: Implication for Their Role in Tumorigenesis 1 1,2 1 1 1 1 1 Li Zeng , Guang-Zhi Wu , Kim Jee Goh , Yew Mun Lee , Chuo Chung Ng , Ang Ben You , Jianhe Wang , 3 3 4 1 Deyong Jia , Aijun Hao , Qiang Yu , Baojie Li * 1 Cancer and Developmental Biology Division, Institute of Molecular and Cell Biology, Singapore, Republic of Singapore, 2 China-Japan Union Hospital, Jilin University, Changchun, Jilin, People’s Republic of China, 3 The Key Laboratory of Experimental Teratology, Ministry of Education, Faculty of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China, 4 Laboratory of Molecular Pharmacology, Genome Institute of Singapore, Singapore, Republic of Singapore 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 HCT