Silencing of NRAGE induces autophagy via AMPK/Ulk1/Atg13 signaling pathway in NSCLC cells

Zhou, Yiyang; Huang, Nan; Wu, Jianchun; Zhen, Ni; Li, Ning; Li, Yan; Li, Yongxin

doi:10.1177/1010428317709676

Cited by 10 publications

(5 citation statements)

References 20 publications

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“…Hence, our new finding that MAGED2 inhibits autophagy only under stressed conditions fits well with an important role of MAGED2, which is restricted to stress conditions. In this respect, our findings with MAGED2 differ from previous studies showing induction of autophagy upon deletion of MAGEA3/A6 in unstressed HeLa and U2OS cells [15], or unstressed MAGED1-depleted A549 and H1299 cells [32]. Given that activation of the cAMP/PKA pathway by forskolin abrogated autophagy in cells exposed to either physical hypoxia or the ER-stressor tunicamycin indicates that the latter stressor (like hypoxia) may also promote endocytosis of Gαs.…”

Section: Discussioncontrasting

confidence: 94%

MAGED2 Depletion Promotes Stress-Induced Autophagy by Impairing the cAMP/PKA Pathway

Nasrah,

Radi,

Daberkow

et al. 2023

IJMS

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Melanoma-associated antigen D2 (MAGED2) plays an essential role in activating the cAMP/PKA pathway under hypoxic conditions, which is crucial for stimulating renal salt reabsorption and thus explaining the transient variant of Bartter’s syndrome. The cAMP/PKA pathway is also known to regulate autophagy, a lysosomal degradation process induced by cellular stress. Previous studies showed that two members of the melanoma-associated antigens MAGE-family inhibit autophagy. To explore the potential role of MAGED2 in stress-induced autophagy, specific MAGED2-siRNA were used in HEK293 cells under physical hypoxia and oxidative stress (cobalt chloride, hypoxia mimetic). Depletion of MAGED2 resulted in reduced p62 levels and upregulation of both the autophagy-related genes (ATG5 and ATG12) as well as the autophagosome marker LC3II compared to control siRNA. The increase in the autophagy markers in MAGED2-depleted cells was further confirmed by leupeptin-based assay which concurred with the highest LC3II accumulation. Likewise, under hypoxia, immunofluorescence in HEK293, HeLa and U2OS cell lines demonstrated a pronounced accumulation of LC3B puncta upon MAGED2 depletion. Moreover, LC3B puncta were absent in human fetal control kidneys but markedly expressed in a fetal kidney from a MAGED2-deficient subject. Induction of autophagy with both physical hypoxia and oxidative stress suggests a potentially general role of MAGED2 under stress conditions. Various other cellular stressors (brefeldin A, tunicamycin, 2-deoxy-D-glucose, and camptothecin) were analyzed, which all induced autophagy in the absence of MAGED2. Forskolin (FSK) inhibited, whereas GNAS Knockdown induced autophagy under hypoxia. In contrast to other MAGE proteins, MAGED2 has an inhibitory role on autophagy only under stress conditions. Hence, a prominent role of MAGED2 in the regulation of autophagy under stress conditions is evident, which may also contribute to impaired fetal renal salt reabsorption by promoting autophagy of salt-transporters in patients with MAGED2 mutation.

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Section: Discussioncontrasting

confidence: 94%

MAGED2 Depletion Promotes Stress-Induced Autophagy by Impairing the cAMP/PKA Pathway

Nasrah,

Radi,

Daberkow

et al. 2023

IJMS

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“…Chung et al found that the Beclin1 played an important role in RANKL‐induced osteoclastogenesis in BMM, and Atg5 was also required for the ruffled border (Chung et al., 2014; Pierrefite‐Carle, Santucci‐Darmanin, Breuil, Camuzard, & Carle, 2015). More importantly, similar to the NRAGE regulated autophagy in lung cancer cells (Zhou et al., 2017), the present study demonstrated mRNA expression of atg5, atg7, atg12, and beclin1 in NRAGE−/− mice is significantly higher compared to WT mice at control, 2, and 4 weeks. The protein expression of ATG5 and ATG7 exhibited similar changes (Figure 5).…”

Section: Discussionsupporting

confidence: 86%

Knockout of NRAGE promotes autophagy‐related gene expression and the periodontitis process in mice

et al. 2020

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Background and Objective Neurotrophin receptor‐interacting MAGE homologue (NRAGE) plays a crucial role in the regulation of bone metabolism. The present study investigated the regulation role of NRAGE on autophagy activation and periodontitis process during experimental periodontitis. Materials and Methods Six‐week‐old wild‐type (WT) and NRAGE−/− mice were randomly divided into three time points in the periodontitis groups (0, 2, and 4 weeks). Histopathological changes were determined using the tooth mobility, hematoxylin and eosin (H&E) staining, and micro‐computed tomography (micro‐CT). Osteoclasts activation and number were investigated using tartrate‐resistant acid phosphatase (TRAP) staining, immunohistochemistry, and real‐time quantitative PCR (RT‐PCR). The level of autophagy‐related gene expression was measured using immunohistochemistry, immunofluorescence, and RT‐PCR. Results H&E staining and Micro‐CT showed that the destruction of the alveolar bone was considerably more severe in the NRAGE−/− group than the WT group after ligation. Tooth mobility in the NRAGE−/− group was obviously higher than that in the WT group. The activation and number of osteoclasts and the level of autophagy‐related gene expression in NRAGE−/− group were significantly higher than that in WT group. Conclusions The present study showed that knockout of NRAGE induced autophagy‐related gene expression and accelerated the process of periodontitis disease via increasing the activity and differentiation of osteoclast.

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“…As a form of type-II programmed cell death, autophagy could lead to cell death through lysosome-related degradation (1,13), which associated with tumorigenesis and cancer cell metabolism in recent literatures (14,15). Inducing cancer cell autophagy could be as a potential strategy to evoke cell death.…”

Section: Introductionmentioning

confidence: 99%

One novel curcumin derivative ZYX01 induces autophagy of human non-small lung cancer cells A549 through AMPK/ULK1/Beclin-1 signaling pathway

Zhou

Wang

et al. 2019

Cell Mol Biol (Noisy-le-grand)

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Presently, curcumin derivatives had been paid more attention in view of their high bioavailability or water solubility, which herein possibly replaced the curcumin for their functional applications in future. Here, one novel chemically synthesized curcumin derivative, ZYX01, was used to identify anti-proliferation activity of human non-small lung cancer cells A549 and its anti-proliferative mechanism. Our study showed that ZYX01 could induce autophagic death of A549 cells by morphological observation, MTT assay, acridine orange staining and MDC assay, which possess a dose-and time-dependent manner. ZYX01-treated A549 cells possessed an increase in LC3-II/LC3-I ratio, upregulation of beclin-1 and downregulation of p62 expression. We further confirmed the cellular AMPK/ULK1/ Beclin-1 signaling pathway in A549 cells after ZYX01 treatment. The anti-migration effect of ZYX01 in A549 cells was also explored by wound healing assay and transwell experiment. Current results had confirmed that ZYX01 induced A549 cells autophagy through AMPK/ULK1/Beclin-1 pathway and shed light on the future study on the anti-cancer molecular mechanism.

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Silencing of NRAGE induces autophagy via AMPK/Ulk1/Atg13 signaling pathway in NSCLC cells

Cited by 10 publications

References 20 publications

MAGED2 Depletion Promotes Stress-Induced Autophagy by Impairing the cAMP/PKA Pathway

MAGED2 Depletion Promotes Stress-Induced Autophagy by Impairing the cAMP/PKA Pathway

Knockout of NRAGE promotes autophagy‐related gene expression and the periodontitis process in mice

One novel curcumin derivative ZYX01 induces autophagy of human non-small lung cancer cells A549 through AMPK/ULK1/Beclin-1 signaling pathway

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