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  3. Free fatty acids derived from lipophagy enhanced resistance to anoikis by activating Src in high-invasive clear cell renal cell carcinoma cells

Free fatty acids derived from lipophagy enhanced resistance to anoikis by activating Src in high-invasive clear cell renal cell carcinoma cells

  • Cell Signal. 2025 Mar:127:111622. doi: 10.1016/j.cellsig.2025.111622.
Mengmeng Wu 1,  Guijuan Chen 1,  Xin Li 1,  Wenliang Ma 2,  Yi Chen 1,  Yi Gong 1,  Hao Zheng 1,  Gongming Gu 1,  Yibing Ding 3,  Ping Dong 1,  Weidong Ding 1,  Luqing Zhang 1,  Weidong Gan 4,  Dongmei Li 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-embryology, Medical School, Nanjing University, Nanjing, Jiangsu 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093, China.
  • 2 Department of Urology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, Jiangsu 210008, China.
  • 3 Translational Medicine Core Facilities, Medical School, Nanjing University, Nanjing, Jiangsu 210093, China.
  • 4 Department of Urology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, Jiangsu 210008, China.. Electronic address: gwd@nju.edu.cn.
  • 5 State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-embryology, Medical School, Nanjing University, Nanjing, Jiangsu 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093, China. Electronic address: lidm@nju.edu.cn.
PMID: 39875047 DOI: 10.1016/j.cellsig.2025.111622
Abstract

Autophagy-mediated anoikis resistance plays a critical role in the initiation of tumor metastasis. Therefore, we investigated the role and mechanism of anoikis resistance mediated by free fatty acids (FFAs) derived from lipophagy in highly invasive clear cell renal cell carcinoma (ccRCC). Here, we found that the highly invasive ccRCC cell line Himi exhibited enhanced resistance to anoikis and elevated lipophagy levels. The increased lipophagy observed in Himi ccRCC cells contributed to their resistance to anoikis. The nonreceptor tyrosine kinase Src was significantly upregulated in Himi cells cultured under suspension conditions and in patients with poor prognoses. The underlying mechanism revealed that the FFAs released from lipophagy activated the phosphorylated Tyr419 site of Src, thereby promoting ccRCC invasion, facilitating epithelial-mesenchymal transition (EMT), enhancing angiogenesis, and conferring resistance to anoikis. Therefore, the present study revealed that FFAs generated from the degradation of lipid droplets via lipophagy enhanced resistance to anoikis by activating the phosphorylated Tyr419 site of Src in highly invasive ccRCC.

Keywords

Anoikis; Clear cell renal cell carcinoma; Free fatty acids; Lipophagy; Src; Tumor metastasis.

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