Retracted: 9za plays cytotoxic and proapoptotic roles and induces cytoprotective autophagy through the PDK1/Akt/mTOR axis in non-small-cell lung cancer |
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Authors: | Rangru Liu Zhuo Chen Xinan Yi Fengying Huang Gaoyun Hu Danqi Liu Xi Li Honghao Zhou Zhaoqian Liu |
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Institution: | 1. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China;2. Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China;3. The United Laboratory for Neurosciences of Hainan Medical University and the Fourth Military Medical University, Haikou, Hainan, China;4. Key Laboratory of Tropical Diseases and Translational Medicine of the Ministry of Education, Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical University, Haikou, Hainan, China;5. Department of Pharmacy, Xiangya Hospital, Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan, China;6. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China
Hunan Key Laboratory of Pharmacogenetics, National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China |
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Abstract: | Non-small-cell lung cancer (NSCLC) is an aggressive subtype of pulmonary carcinomas with high mortality. However, chemotherapy drug resistance and high recurrence rates hinder the curative effect of platinum-based first-line chemotherapy, which makes it urgent to develop new antitumor drugs for NSCLC. 9za, a new candidate drug synthesized by our research group, has been verified with potent antilung cancer activity in preliminary experiments. However, the underlying molecular mechanism of 9za remains largely vague. This work revealed that 9za could play important cytotoxic and proapoptotic roles in NSCLC cells. Moreover, 9za could induce autophagy and promote autophagy flux. Interestingly, the cytotoxic and proapoptotic roles were significantly dependent on 9za-induced cytoprotective autophagy. That is, the coadministration of 9za with an autophagy inhibitor such as chloroquine or 3-methyladenine exhibited increased cytotoxic and proapoptotic effects compared with 9za treatment alone. In addition, 9za exposure suppressed the phosphorylation of phosphoinositide-dependent protein kinase 1 (PDK1), protein kinase B (Akt), mammalian targets of rapamycin (mTOR), p70 S6 kinase, and 4E binding protein 1 by a dose-dependent way, manifesting that the Akt/mTOR axis was implicated in 9za-induced autophagy. In addition, the overexpression of PDK1 resulted in increased phosphorylation of PDK1 and Akt and blocking of 9za-mediated autophagy. These data showed that the PDK1/Akt/mTOR pathway was involved in 9za-induced autophagy. Hence, this work provides a theoretical basis for exploiting 9za as a new antilung cancer candidate drug and hints that the combination of 9za with an autophagy inhibitor is a feasible alternative approach for the therapy of NSCLC. |
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Keywords: | 9za autophagy cytotoxicity non-small-cell lung cancer PDK1/Akt/mTOR signaling pathway |
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