9za plays cytotoxic and proapoptotic roles and induces cytoprotective autophagy through the PDK1/Akt/mTOR axis in non-small-cell lung cancer.

Authors:
Zhuo Chen
Zhuo Chen
State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering
United States
Xinan Yi
Xinan Yi
Hainan Medical University
Fengying Huang
Fengying Huang
Second Xiangya Hospital
China
Gaoyun Hu
Gaoyun Hu
Central South University
China
Danqi Liu
Danqi Liu
The Third Xiangya Hospital of Central South University
Xi Li
Xi Li
National Clinical Research Center of Cardiovascular Diseases
Winston-Salem | United States
Honghao Zhou
Honghao Zhou
Central South University
China

J Cell Physiol 2019 Apr 19. Epub 2019 Apr 19.

Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China.

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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http://dx.doi.org/10.1002/jcp.28679DOI Listing
April 2019
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