Inhibiting eEF-2 kinase-mediated autophagy enhanced the cytocidal effect of AKT inhibitor on human nasopharyngeal carcinoma

• Published in: Drug design, development and therapy development and therapy, 2018-01, Vol.12, p.2655-2663
• Main Authors: Zhao, Yuan-Yuan, Tian, Ying, Liu, Lin, Zhan, Jian-Hua, Hou, Xue, Chen, Xi, Zhou, Ting, Huang, Yan, Zhang, Li
• Format: Article
• Language: English
• Subjects: AKT; AKT protein; Animals; Anticancer properties; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor activity; Apoptosis; Apoptosis - drug effects; Autophagy; Biotechnology; Cancer; Cancer therapies; Cancer treatment; Carcinoma; Cell proliferation; Cell Proliferation - drug effects; Cell Survival - drug effects; Deactivation; Drug Screening Assays, Antitumor; eEF-2 kinase; Elongation; Elongation Factor 2 Kinase - antagonists & inhibitors; Elongation Factor 2 Kinase - metabolism; Enzyme inhibitors; Epstein-Barr virus; Experiments; Heterocyclic Compounds, 3-Ring - chemistry; Heterocyclic Compounds, 3-Ring - pharmacology; Humans; Hydroxychloroquine; Hypoxia; Imidazoles - chemistry; Imidazoles - pharmacology; Immunoglobulins; Inactivation; Inhibition; Inhibitors; Kinases; Laboratories; Male; Melanoma; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; Nasopharyngeal carcinoma; Nasopharyngeal Neoplasms - drug therapy; Nasopharyngeal Neoplasms - metabolism; Nasopharyngeal Neoplasms - pathology; Oncology; Original Research; Phagocytosis; Phosphorylation; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Proteins; Synergistic effect; Throat cancer; Tumor Cells, Cultured; Tumors; Viruses; Western blotting; Xenografts; Xenotransplantation
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/DDDT.S169952

Our previous research showed that AKT inactivation via small molecule inhibitors did not induce significant apoptosis, but rather markedly increased autophagy in nasopharyngeal carcinoma (NPC). The purpose of the current study was to determine whether autophagy inhibition can enhance the anticancer efficacy of an AKT inhibitor (MK-2206). NPC cell lines CNE-2 (Epstein-Barr virus negative) and C666-1 (Epstein-Barr virus positive) were used to conduct the research. Autophagy induction effects were evaluated via Western blotting. Eukaryotic elongation factor-2 (eEF-2) kinase was specifically and stably knocked down using shRNA. The growth and proliferation of the cells were assessed by Cell Counting Kit-8. In CNE-2 xenograft tumors, the antitumor effects of an AKT inhibitor (MK-2206) combined with an eEF-2 kinase inhibitor (NH125) were tested. MK-2206 induced eEF-2 kinase-dependent autophagy in NPC cell lines. Knockdown of eEF-2 kinase using shRNA blunted the autophagy activated by MK-2206. Compared with treatment with MK-2206 alone, shRNA or NH125 suppressed eEF-2 kinase and increased the growth-inhibitory effect of MK-2206 on the human NPC cell lines. The synergistic effects of eEF-2 kinase inhibition and MK-2206 were similar to those of the combination of hydroxychloroquine and MK-2206. Moreover, NH125 showed good synergistic effects with MK-2206 in vivo. eEF-2 kinase-mediated autophagy induced by AKT inhibition played a protective role in NPC cells. Inhibition of eEF-2 kinase may be an effective method for increasing the efficacy of an AKT inhibitor such as MK-2206 in NPC.