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.

Autor: Katreddy RR; Department of Biology and Biochemistry, College of Natural Sciences and Mathematics, University of Houston, Houston, TX, 77204, USA., Bollu LR; Department of Biology and Biochemistry, College of Natural Sciences and Mathematics, University of Houston, Houston, TX, 77204, USA., Su F; Department of Biology and Biochemistry, College of Natural Sciences and Mathematics, University of Houston, Houston, TX, 77204, USA., Xian N; Immunotherapy Institute, Fujian Medical University, University Town, Fuzhou, Fujian, 350122, China., Srivastava S; Department of Biology and Biochemistry, College of Natural Sciences and Mathematics, University of Houston, Houston, TX, 77204, USA., Thomas R; Department of Biology and Biochemistry, College of Natural Sciences and Mathematics, University of Houston, Houston, TX, 77204, USA., Dai Y; Department of Biology and Biochemistry, College of Natural Sciences and Mathematics, University of Houston, Houston, TX, 77204, USA., Wu B; Immunotherapy Institute, Fujian Medical University, University Town, Fuzhou, Fujian, 350122, China., Xu Y; Immunotherapy Institute, Fujian Medical University, University Town, Fuzhou, Fujian, 350122, China., Rea MA; Department of Biology and Biochemistry, College of Natural Sciences and Mathematics, University of Houston, Houston, TX, 77204, USA., Briggs JM; Department of Biology and Biochemistry, College of Natural Sciences and Mathematics, University of Houston, Houston, TX, 77204, USA., Zhang Q; Department of Medical Oncology, Cancer Hospital of Harbin Medical University, Harbin Medical University, 150081, Harbin, Heilongjiang, China., Lu X; Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Huang G; Immunotherapy Institute, Fujian Medical University, University Town, Fuzhou, Fujian, 350122, China. gangxiong.huang@fjmu.edu.cn.; Suzhou Institute, Xi'an Jiaotong University, Suzhou, Jiangsu, 215123, China. gangxiong.huang@fjmu.edu.cn., Weihua Z; Department of Biology and Biochemistry, College of Natural Sciences and Mathematics, University of Houston, Houston, TX, 77204, USA. wzhang13@uh.edu.
Jazyk: angličtina
Zdroj: Oncogenesis [Oncogenesis] 2018 Jan 23; Vol. 7 (1), pp. 5. Date of Electronic Publication: 2018 Jan 23.
DOI: 10.1038/s41389-017-0021-7
Abstrakt: 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.
Databáze: MEDLINE
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