Abstract 3558: Src regulation of peroxisome proliferator-activated receptor gamma (PPARγ) in lipid metabolism of lung cancer

Metabolic reprogramming, recently becoming one of the cancer hallmarks, is linked to oncogenic signal transduction to find a better solution for cancer therapy. As one of key mediators in oncogenic signal transduction, non-receptor tyrosine kinase Src is known to drive cancer progression by promoting cell proliferation, metastasis, and drug resistance. Although previous studies reported that Src promotes fat accumulation and suppresses browning of white adipocytes, little is known about the mechanistic role of Src in cancer metabolism. Here we report that Src mediates lipid mobilization by suppressing transcriptional activity of PPARγ, a key regulator of lipid metabolism. Firstly, we found Src suppression of PPARγ activity which, interestingly, turned out to be independent of Src kinase domain or a known Src phosphorylation site of PPARγ at tyrosine 78. Since the treatment of Src inhibitor (e.g., SU6656, PP2) could rescue Src-driven PPARγ suppression by possibly changing Src conformation, we might suggest the involvement of Src-PPARγ interaction in the regulatory mechanism. Mechanistically, further in vitro experiment showed Src inhibitor treatment recovered expression of PPARγ target genes such as fatty acid binding protein 4 (FABP4) and cluster of differentiation 36 (CD36) in a subset of non-small cell lung cancer cell lines. The increase of FABP4 and CD36 expression was associated with the reduction of lipid droplets, suggesting the role of Src regulation of PPARγ in lipid mobilization. Collectively, this finding provides better understandings about the role of Src in cancer lipid metabolism, and an insight into therapeutic combination of targeting oncogenic signal transduction and lipid metabolism to treat cancer. Note: This abstract was not presented at the meeting. Citation Format: Tuyen N. M. Hua, Ai N. H. Phan, Yangsik Jeong. Src regulation of peroxisome proliferator-activated receptor gamma (PPARγ) in lipid metabolism of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3558. doi:10.1158/1538-7445.AM2017-3558