LZ-101, a novel derivative of danofloxacin, induces mitochondrial apoptosis by stabilizing FOXO3a via blocking autophagy flux in NSCLC cells

Guo, Yongjian; Zhao, Yue; Zhou, Yuxin; Tang, Xiaoqing; Li, Zhiyu; Wang, Xiaotang

doi:10.1038/s41419-019-1714-y

Cited by 16 publications

(9 citation statements)

References 34 publications

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“…We also found that the decreased cell viability by pitavastatin in cells was partially recovered upon FOXO3a gene silencing ( Figure 4G ). This result was consistent with the recent finding, wherein the accumulation of FOXO3a protein by the blockade of autophagy flux causes mitochondrial apoptosis in non-small-cell-lung carcinoma ( Guo et al, 2019 ).…”

Section: Discussionsupporting

confidence: 94%

Pitavastatin Induces Cancer Cell Apoptosis by Blocking Autophagy Flux

Pun

Lee²,

Song³

et al. 2022

Front. Pharmacol.

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Statins, a class of lipid-lowering drugs, are used in drug repositioning for treatment of human cancer. However, the molecular mechanisms underlying statin-induced cancer cell death and autophagy are not clearly defined. In the present study, we showed that pitavastatin could increase apoptosis in a FOXO3a-dependent manner in the oral cancer cell line, SCC15, and the colon cancer cell line, SW480, along with the blockade of autophagy flux. The inhibition of autophagy by silencing the LC3B gene reduced apoptosis, while blockade of autophagy flux using its inhibitor, Bafilomycin A1, further induced apoptosis upon pitavastatin treatment, which suggested that autophagy flux blockage was the cause of apoptosis by pitavastatin. Further, the FOXO3a protein accumulated due to the blockade of autophagy flux which in turn was associated with the induction of ER stress by transcriptional upregulation of PERK-CHOP pathway, subsequently causing apoptosis due to pitavastatin treatment. Taken together, pitavastatin-mediated blockade of autophagy flux caused an accumulation of FOXO3a protein, thereby leading to the induction of PERK, ultimately causing CHOP-mediated apoptosis in cancer cells. Thus, the present study highlighted the additional molecular mechanism underlying the role of autophagy flux blockade in inducing ER stress, eventually leading to apoptosis by pitavastatin.

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Section: Discussionsupporting

confidence: 94%

Pitavastatin Induces Cancer Cell Apoptosis by Blocking Autophagy Flux

Pun

Lee²,

Song³

et al. 2022

Front. Pharmacol.

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“…For example, FOXO3a is negatively regulated by miR-155 in ischemic renal diseases and some types of cancer ( 43 ); by miR-132, miR-212 and miR-223 in inflammatory bowel disease ( 44 ); by miR-27a in glioblastoma cells ( 45 ); by miR-132 and miR-212 in Alzheimer's disease, leading to neuronal apoptosis ( 46 ); and by miR-205 in lung cancer cells ( 47 ). A number of in vitro and in vivo studies have shown promising results of FOX3a-targeting cancer therapy for lung cancer ( 48 – 50 ). Interestingly, cordycepin triggers the re-localization of FOXO3a protein from the nucleus to the cytoplasm in lung cancer cells ( 51 ).…”

Section: Discussionmentioning

confidence: 99%

Nicotine‑induced miR‑21‑3p promotes chemoresistance in lung cancer by negatively regulating FOXO3a

et al. 2022

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Lung cancer is the leading cause of cancer-related mortality worldwide and cigarette smoking is reported to contribute to the lung cancer-related mortality. The present study aimed to investigate the molecular mechanism underlying nicotine-induced chemoresistance in lung cancer. The expression of microRNA (miR)-21-3p and its predicted target FOXO3a in lung cancer cells was detected via reverse transcription-quantitative PCR, in the presence or absence of nicotine. The regulatory effect of miR-21-3p and FOXO3a on lung cancer cell proliferation and apoptosis induced by docetaxel or cisplatin treatment was evaluated by performing Cell Counting Kit-8 and Annexin V/PI staining assays, respectively. The interaction between miR-21-3p and FOXO3a was analyzed by performing luciferase reporter assays and western blotting. FOXO3a overexpression rescue experiments were conducted in vitro and in vivo using a xenograft mouse model to assess the function of miR-21-3p/FOXO3a in lung cancer. Nicotine induced miR-21-3p expression in lung cancer cells in a dose-dependent manner. miR-21-3p downregulated FOXO3a expression by directly binding to the 3′-untranslated region of FOXO3a. Moreover, miR-21-3p knockdown sensitized lung cancer cells to docetaxel or cisplatin treatment. Mechanistically, FOXO3a was predicted as a direct target of miR-21-3p. FOXO3a overexpression promoted the chemosensitivity of lung cancer cells to docetaxel or cisplatin treatment. Furthermore, FOXO3a overexpression antagonized the regulatory function of miR-21-3p on docetaxel- or cisplatin-treated lung cancer cells. In the docetaxel- or cisplatin-treated lung cancer xenograft mouse model, miR-21-3p promoted chemoresistance via negatively regulating FOXO3a. Therefore, the present study demonstrated that nicotine-induced miR-21-3p promoted chemoresistance to docetaxel or cisplatin treatment via negatively regulating FOXO3a, which may serve as a novel therapeutic strategy for the treatment of patients with chemoresistant lung cancer.

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“…It not only has the function of redox and electron transfer, but also can promote apoptosis, which plays an important role in maintaining the normal physiological activities of cells. Under the stimulation of exogenous death trigger signal, AIF was released from mitochondria to cytoplasm and then into nuclear, which induced caspase-independent apoptosis 15 , 16 . The release of AIF from mitochondria can be regulated by many factors.…”

Section: Discussionmentioning

confidence: 99%

“…Mitochondria are the key factors in the initiation and execution of apoptosis 13 , 14 . When stimulated by a series of external signals, mitochondria releases apoptosis-inducing factors such as AIF, endonuclease G and Cytochrome c into the cytoplasm, and activating caspase-dependent or caspase-independent pathways to induce apoptosis 15 , 16 . AIF is anchored to the inner membrane of mitochondria and performs the function of oxidoreductase under normal physiological conditions.…”

Section: Introductionmentioning

confidence: 99%

PAK5-mediated AIF phosphorylation inhibits its nuclear translocation and promotes breast cancer tumorigenesis

Yao¹,

Li²,

Hu³

et al. 2021

Int. J. Biol. Sci.

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Although p21 activated kinase 5 (PAK5) is related to the progression of multiple cancers, its biological function in breast cancer remains unclear. Apoptosis-inducing factor (AIF) is a vital apoptosis factor in mitochondria, which can be released from mitochondria and enter the nucleus, causing caspase-independent apoptosis. In this study, we reveal that PAK5 inhibits apoptosis by preventing the nuclear translocation of AIF. PAK5 inhibits the release of AIF from mitochondria in breast cancer cells by decreasing the mitochondria membrane permeability and increasing the membrane potential. Furthermore, PAK5 phosphorylates AIF at Thr281 site to inhibit the formation of AIF/importin α3 complex, leading to decrease AIF nuclear translocation. Functionally, we demonstrate that PAK5-mediated AIF phosphorylation promotes the proliferation of breast cancer cells and accelerates the growth of breast cancer in vivo . Significantly, PAK5 and AIF expression in breast cancer are positively correlated with poor patient prognosis. PAK5 expression is negatively correlated with AIF nuclear translocation. These results suggest that PAK5-AIF signaling pathway may play an essential role in mammary tumorigenesis, providing a new therapeutic target for the treatment of breast cancer.

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LZ-101, a novel derivative of danofloxacin, induces mitochondrial apoptosis by stabilizing FOXO3a via blocking autophagy flux in NSCLC cells

Cited by 16 publications

References 34 publications

Pitavastatin Induces Cancer Cell Apoptosis by Blocking Autophagy Flux

Pitavastatin Induces Cancer Cell Apoptosis by Blocking Autophagy Flux

Nicotine‑induced miR‑21‑3p promotes chemoresistance in lung cancer by negatively regulating FOXO3a

PAK5-mediated AIF phosphorylation inhibits its nuclear translocation and promotes breast cancer tumorigenesis

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