Department of Oncology, The Affiliated Wujin Hospital, Jiangsu University, Changzhou, Jiangsu, China.
School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China.
J Cell Biochem. 2021 Apr;122(3-4):394-402. doi: 10.1002/jcb.29868. Epub 2020 Nov 8.
Epidermal growth factor receptor (EGFR) induces peroxisome-proliferator-activated receptor-δ (PPARδ)-Y108 phosphorylation, while it is unclear the effect of phosphorylation of PPARδ on cancer cell metabolism. Here we found that EGF treatment increased its protein stability by inhibiting its lysosomal dependent degradation, which was reduced by gefitinib (EGFR inhibitor) treatment. PPARδ-Y108 phosphorylation in response to EGF recruited HSP90 (heat shock protein 90) to PPARδ resulting in increased PPARδ stability. In addition, PPARδ-Y108 phosphorylation promoted cancer cell metabolism, proliferation, and chemoresistance. Therefore, this study revealed a novel molecular mechanism of EGFR/HSP90/PPARδ pathway-mediated cancer cell metabolism, proliferation, and chemoresistance, which provides a strategy for cancer treatment.
表皮生长因子受体（EGFR）诱导过氧化物酶体增殖物激活受体-δ（PPARδ）-Y108 磷酸化，而磷酸化的 PPARδ 对癌细胞代谢的影响尚不清楚。在这里，我们发现 EGF 通过抑制其溶酶体依赖性降解来增加其蛋白稳定性，而 gefitinib（EGFR 抑制剂）处理则降低了其蛋白稳定性。EGF 诱导的 PPARδ-Y108 磷酸化募集 HSP90（热休克蛋白 90）到 PPARδ 上，从而增加了 PPARδ 的稳定性。此外，PPARδ-Y108 磷酸化促进了癌细胞的代谢、增殖和化疗耐药性。因此，本研究揭示了 EGFR/HSP90/PPARδ 通路介导的癌细胞代谢、增殖和化疗耐药性的新分子机制，为癌症治疗提供了一种策略。
