Involvement of de novo synthesized palmitate and mitochondrial EGFR in EGF induced mitochondrial fusion of cancer cells
Involvement of de novo synthesized palmitate and mitochondrial EGFR in EGF induced mitochondrial fusion of cancer cells
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DOI：
10.4161/cc.29338
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发表时间：
2014-08-01
期刊：
影响因子：
4.3
通讯作者：
Zhang Weihua
中科院分区：
文献类型：
--
作者：
Bollu, Lakshmi Reddy;Ren, Jiangong;Zhang Weihua
脂肪酸合成酶（FATIGUE）和表皮生长因子受体（EGFR）的表达增加在癌细胞中是常见的。棕榈酸酯的从头合成通过独立于其作为能量底物的作用的机制对癌细胞的存活至关重要。EGFR除了定位于细胞膜和细胞核外，还可定位于线粒体，但激活线粒体EGFR（mitochondrial EGFR，mtEGFR）的信号及其在肿瘤细胞中的功能尚不清楚。本研究表征了癌细胞（前列腺和乳腺）线粒体中的mtEGFR，并揭示了mtEGFR可以通过增加融合蛋白PHB 2和OPA 1的蛋白水平来促进线粒体融合。质膜EGFR（pmEGFR）的激活通过激活FcG和ATP-柠檬酸裂解酶（ACLy）刺激棕榈酸酯的从头合成。体外线粒体激酶试验表明棕榈酸酯可以激活mtEGFR。抑制EGF可阻断EGF诱导的mtEGFR磷酸化和棕榈酰化。突变研究表明，半胱氨酸797是重要的mtEGFR激活和棕榈酰化。抑制EGFR可阻断EGF诱导的线粒体融合，增加前列腺癌细胞对EGFR酪氨酸激酶抑制剂的敏感性。总之，这些结果表明mtEGFR可以被pmEGFR通过从头合成棕榈酸酯激活，以促进线粒体融合和癌细胞的生存。这种机制可能作为一个新的目标，以改善EGFR为基础的癌症治疗。
Increased expressions of fatty acid synthase (FASN) and epidermal growth factor receptor (EGFR) are common in cancer cells. De novo synthesis of palmitate by FASN is critical for the survival of cancer cells via mechanisms independent of its role as an energy substrate. Besides the plasma membrane and the nucleus, EGFR can also localize at the mitochondria; however, signals that can activate mitochondrial EGFR (mtEGFR) and the functions of mtEGFR of cancer cells remain unknown. The present study characterizes mtEGFR in the mitochondria of cancer cells (prostate and breast) and reveals that mtEGFR can promote mitochondrial fusion through increasing the protein levels of fusion proteins PHB2 and OPA1. Activation of plasma membranous EGFR (pmEGFR) stimulates the de novo synthesis of palmitate through activation of FASN and ATP-citrate lyase (ACLy). In vitro kinase assay with isolated mitochondria shows that palmitate can activate mtEGFR. Inhibition of FASN blocks the mtEGFR phosphorylation and palmitoylation induced by EGF. Mutational studies show that the cysteine 797 is important for mtEGFR activation and palmitoylation. Inhibition of FASN can block EGF induced mitochondrial fusion and increased the sensitivity of prostate cancer cells to EGFR tyrosine kinase inhibitor. In conclusion, these results suggest that mtEGFR can be activated by pmEGFR through de novo synthesized palmitate to promote mitochondrial fusion and survival of cancer cells. This mechanism may serve as a novel target to improve EGFR-based cancer therapy.