Wu Mengmeng, Chen Guijuan, Li Xin, Ma Wenliang, Chen Yi, Gong Yi, Zheng Hao, Gu Gongming, Ding Yibing, Dong Ping, Ding Weidong, Zhang Luqing, Gan Weidong, Li Dongmei
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.
Department of Urology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, Jiangsu 210008, China.
Cell Signal. 2025 Mar;127:111622. doi: 10.1016/j.cellsig.2025.111622. Epub 2025 Jan 26.
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.
自噬介导的失巢凋亡抗性在肿瘤转移起始中起关键作用。因此，我们研究了脂噬产生的游离脂肪酸（FFA）介导的失巢凋亡抗性在高侵袭性透明细胞肾细胞癌（ccRCC）中的作用及机制。在此，我们发现高侵袭性ccRCC细胞系Himi对失巢凋亡的抗性增强且脂噬水平升高。在Himi ccRCC细胞中观察到的脂噬增加导致其对失巢凋亡产生抗性。非受体酪氨酸激酶Src在悬浮培养的Himi细胞以及预后不良的患者中显著上调。潜在机制表明，脂噬释放的FFA激活了Src的磷酸化Tyr419位点，从而促进ccRCC侵袭、促进上皮-间质转化（EMT）、增强血管生成并赋予对失巢凋亡的抗性。因此，本研究表明，在高侵袭性ccRCC中，通过脂噬降解脂滴产生的FFA通过激活Src的磷酸化Tyr419位点增强了对失巢凋亡的抗性。
