Targeted reduction of the EGFR protein, but not inhibition of its kinase activity, induces mitophagy and death of cancer cells through activation of mTORC2 and Akt.
Targeted reduction of the EGFR protein, but not inhibition of its kinase activity, induces mitophagy and death of cancer cells through activation of mTORC2 and Akt.
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DOI：
10.1038/s41389-017-0021-7
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发表时间：
2018-01-23
期刊：
影响因子：
6.2
通讯作者：
Weihua Z
中科院分区：
文献类型：
--
作者：
Katreddy RR;Bollu LR;Su F;Xian N;Srivastava S;Thomas R;Dai Y;Wu B;Xu Y;Rea MA;Briggs JM;Zhang Q;Lu X;Huang G;Weihua Z
致癌表皮生长因子受体（EGFR）通常在实体癌中过度表达。 EGFR 的酪氨酸激酶活性一直是癌症的主要治疗靶点；然而，EGFR 酪氨酸激酶抑制剂治疗癌症的功效在临床上受到先天性和获得性耐药的挑战。越来越多的证据表明 EGFR 具有不依赖于激酶的促生存功能，并且癌细胞更容易受到 EGFR 蛋白减少的影响，而不是其激酶活性的抑制。 EGFR 缺失引起的细胞死亡的分子机制仍然很大程度上未知。在这项研究中，我们发现，与抑制 EGFR 激酶活性（已知会诱导促存活的非选择性自噬）不同，通过 siRNA 或合成的 EGFR 下调肽（Herdegradin）下调 EGFR 蛋白，通过激活 mTORC2/Akt 轴，通过选择性线粒体自噬杀死前列腺和卵巢癌细胞。此外，Herdegradin 诱导线粒体自噬并抑制小鼠原位卵巢癌的生长。这项研究将抗线粒体自噬确定为 EGFR 的激酶独立功能，揭示了 mTORC2/Akt 轴在促进癌细胞线粒体自噬中的新功能，并为 EGFR 蛋白的药理学下调作为 EGFR 阳性癌症的潜在治疗提供了一种新方法。
The oncogenic epidermal growth factor receptor (EGFR) is commonly overexpressed in solid cancers. The tyrosine kinase activity of EGFR has been a major therapeutic target for cancer; however, the efficacy of EGFR tyrosine kinase inhibitors to treat cancers has been challenged by innate and acquired resistance at the clinic. Accumulating evidence suggests that EGFR possesses kinase-independent pro-survival functions, and that cancer cells are more vulnerable to reduction of EGFR protein than to inhibition of its kinase activity. The molecular mechanism underlying loss-of-EGFR-induced cell death remains largely unknown. In this study, we show that, unlike inhibiting EGFR kinase activity that is known to induce pro-survival non-selective autophagy, downregulating EGFR protein, either by siRNA, or by a synthetic EGFR-downregulating peptide (Herdegradin), kills prostate and ovarian cancer cells via selective mitophagy by activating the mTORC2/Akt axis. Furthermore, Herdegradin induced mitophagy and inhibited the growth of orthotopic ovarian cancers in mice. This study identifies anti-mitophagy as a kinase-independent function of EGFR, reveals a novel function of mTORC2/Akt axis in promoting mitophagy in cancer cells, and offers a novel approach for pharmacological downregulation of EGFR protein as a potential treatment for EGFR-positive cancers.
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影响因子：
64.5
作者：
Tan X;Thapa N;Sun Y;Anderson RA
通讯作者：
Anderson RA
AMP激活的蛋白激酶对ULK1（HATG1）的磷酸化将能量传感连接到线粒体。
DOI：
10.1126/science.1196371
发表时间：
2011-01-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Egan DF;Shackelford DB;Mihaylova MM;Gelino S;Kohnz RA;Mair W;Vasquez DS;Joshi A;Gwinn DM;Taylor R;Asara JM;Fitzpatrick J;Dillin A;Viollet B;Kundu M;Hansen M;Shaw RJ
通讯作者：
Shaw RJ
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
4.7
作者：
Melosky B
通讯作者：
Melosky B
影响因子：
3.6
作者：
Fung, Christopher;Chen, Xing;Duvvuri, Umamaheswar
通讯作者：
Duvvuri, Umamaheswar