Tyrosine kinase receptor EGFR regulates the switch in cancer cells between cell survival and cell death induced by autophagy in hypoxia
Tyrosine kinase receptor EGFR regulates the switch in cancer cells between cell survival and cell death induced by autophagy in hypoxia
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DOI：
10.1080/15548627.2016.1164357
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发表时间：
2016-01-01
期刊：
影响因子：
13.3
通讯作者：
Gibson, Spencer B.
中科院分区：
文献类型：
--
作者：
Chen, Yongqiang;Henson, Elizabeth S.;Gibson, Spencer B.
自噬是一种细胞内溶酶体降解途径，其主要功能是使细胞在应激条件下生存。然而，自噬是一把双刃剑，既可以促进细胞存活，也可以促进细胞死亡。在癌症中，缺氧区域会导致预后不良，因为癌细胞能够部分通过自噬来适应缺氧。相反，自噬可能导致癌细胞缺氧诱导的细胞死亡。在这项研究中，我们发现缺氧期间自噬增加。缺氧4小时后，自噬促进细胞存活，而缺氧48小时后，自噬增加细胞死亡。此外，我们发现缺氧16小时后EGFR（表皮生长因子受体）的酪氨酸磷酸化降低。此外，缺氧条件下 4 小时时 EGFR 与 BECN1 的结合显着高于 72 小时。敲低或抑制 EGFR 会导致自噬增加，从而导致缺氧下细胞死亡增加。相反，当通过添加EGF重新激活EGFR时，自噬水平降低，从而导致细胞死亡减少。缺氧导致脂筏蛋白 CAV1（caveolin 1）的自噬降解，已知该蛋白在缺氧期间以不依赖配体的方式结合并激活 EGFR。通过敲低CAV1，缺氧时EGFR磷酸化量减少，自噬和细胞死亡量增加。这就说明 EGFR 的激活在缺氧条件下自噬诱导的细胞生存与细胞死亡的转换中发挥着关键作用。
Autophagy is an intracellular lysosomal degradation pathway where its primary function is to allow cells to survive under stressful conditions. Autophagy is, however, a double-edge sword that can either promote cell survival or cell death. In cancer, hypoxic regions contribute to poor prognosis due to the ability of cancer cells to adapt to hypoxia in part through autophagy. In contrast, autophagy could contribute to hypoxia induced cell death in cancer cells. In this study, we showed that autophagy increased during hypoxia. At 4 h of hypoxia, autophagy promoted cell survival whereas, after 48 h of hypoxia, autophagy increased cell death. Furthermore, we found that the tyrosine phosphorylation of EGFR (epidermal growth factor receptor) decreased after 16 h in hypoxia. Furthermore, EGFR binding to BECN1 in hypoxia was significantly higher at 4 h compared to 72 h. Knocking down or inhibiting EGFR resulted in an increase in autophagy contributing to increased cell death under hypoxia. In contrast, when EGFR was reactivated by the addition of EGF, the level of autophagy was reduced which led to decreased cell death. Hypoxia led to autophagic degradation of the lipid raft protein CAV1 (caveolin 1) that is known to bind and activate EGFR in a ligand-independent manner during hypoxia. By knocking down CAV1, the amount of EGFR phosphorylation was decreased in hypoxia and amount of autophagy and cell death increased. This indicates that the activation of EGFR plays a critical role in the switch between cell survival and cell death induced by autophagy in hypoxia.