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

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 Abbreviations: Akt, protein kinase B; ATG5, autophagy-related gene 5; BrdU, bromodeoxyuridine; CCK-8, cell counting kit-8; CQ, chloroquine; 4EBP1, 4E binding protein 1; LAMP1, lysosomal associated membrane protein 1; LC3, microtubule-associated protein 1 light chain 3; 3-MA, 3-methyladenine; mTOR, mammalian targets of rapamycin; NSCLC, non-small-cell lung cancer; PARP, poly (ADP-ribose) polymerase; PDK1, phosphoinositide-dependent protein kinase 1; PI, propidium iodide; p70S6K, p70 S6 kinase; RAPA, rapamycin; SQSTM1, sequestosome 1; Z-VADfmk, Z-Val-Ala-Asp-fluoromethylketone. SUPPORTING INFORMATIONAdditional supporting information may be found online in the Supporting Information section at the end of the article.How to cite this article: Liu R, Chen Z, Yi X, et al. 9za plays cytotoxic and proapoptotic roles and induces cytoprotective autophagy through the PDK1/Akt/mTOR axis in non-smallcell lung cancer.

<p>Knockdown of circPRKCA Restrained Cell Growth, Migration, and Invasion of NSCLC Cells Both in vitro and in vivo via Regulating miR-330-5p/PDK1/AKT Pathway</p>

“…In NSCLC, targeting the PDK1/PI3K/AKT pathway seemed popular in the treatment of miRNAs 39,40 and drugs. 41,42 Here, this study supported the high activation of AKT signal in NSCLC cells, accompanied with PDK1 upregulation. However, Ding et al 43 considered that miR-199a could block PDK1 expression without affecting AKT activation in NSCLC cells under hypoxia.…”

A novel dual MEK/PDK1 inhibitor 9za retards the cell cycle at G0/G1 phase and induces mitochondrial apoptosis in non-small cell lung cancer cells

“…The novel type of dual inhibitors includes a diphenylamine main frame of PD0325901, which was designated to preserve the MEK hydrophobicity, and an indolone core skeleton, which was appointed to maintain the suppressive activity against PDK1. Our previous work confirmed that 9za can induce autophagy through PDK1/Akt/mTOR signaling pathway (Liu et al, 2019b). This work further verified that 9za is indeed a dual inhibitor against MEK/ERK and PDK1/Akt signaling axes.…”

“…2A) showed the most potent anti-cancer activity among 43 new compounds in NSCLC cells so that it was selected for further research. Our previous study showed that 9za promoted autophagy via the PDK1/Akt/mTOR signal pathway and that autophagy played a pivotal role in 9za-induced cytotoxicity and pro-apoptosis in NSCLC cells (Liu et al, 2019b). However, the exact underlying mechanism of pro-apoptosis for 9za is unclear until now.…”

HIF-1α Regulates Glucocorticoid-Induced Osteoporosis Through PDK1/AKT/mTOR Signaling Pathway

“…Several studies have reported that PDK1 regulates cellular metabolism by activating the AKT/mTOR pathway (30)(31)(32). Adenoviral -PDK1 construct or adenoviral -NC construct was transduced into MC3T3-E1 cells before exposure to dexamethasone.…”