Autophagic Flux Is Regulated by Interaction Between the C-terminal Domain of PATCHED1 and ATG101

Chen, Xiaole; Morales-Alcala, Cintli C.; Galdo, Natalia A. Riobo-Del

doi:10.1158/1541-7786.mcr-17-0597

Cited by 10 publications

(18 citation statements)

References 33 publications

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“…In line with the rescue experiment, miRNA-342-5p might activate fibrotic responses in the kidney by interacting with Ptch1, which is directly regulated by FoxO3. As reported previously, Ptch1 has therapeutic implications in Hh-dependent cancers by inhibiting autophagy ( Chen et al, 2018 ). Autophagy can maintain cell homeostasis and energy under different physiological states ( Klionsky, 2007 ).…”

Section: Discussionsupporting

confidence: 58%

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Regulation of Ptch1 by miR-342-5p and FoxO3 Induced Autophagy Involved in Renal Fibrosis

Tang

Wang

Xie

et al. 2020

Front. Bioeng. Biotechnol.

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The pathogenesis of renal fibrosis (RF) is not well understood. Here, we performed an integrative database analysis of miRNAs and mRNAs to discover the major regulatory pathway in RF. Putative miRNAs and mRNAs involved in RF in unilateral ureteral obstruction (UUO) model mice were extracted and analyzed using the Gene Expression Omnibus (GEO) database. The bioinformatics analysis suggested that Ptch1 expression is regulated by miR-342-5p and FoxO3. Then real-time PCR, Western blot, Fluorescence in situ hybridization were done to confirm the hypothesis. Sixty-three differentially expressed miRNAs (DE-miRNAs) in GSE118340, 141 DE-miRNAs in GSE42716, and 183 DE-mRNAs in GSE69101 were identified. Various bioinformatic analyses revealed miR-342-5p as a strong candidate regulator in RF. We also predicted that miR-342-5p targets Ptch1 and that FoxO3 is the transcription factor of Ptch1. We also observed that TGF-β1 upregulated the expression of miR-342-5p and inhibited the expression of FoxO3 and Ptch1 in TCMK-1 cells. Furthermore, downregulation of miR-342-5p reversed the inhibitory effect of TGF-β1 on the expression of Ptch1 in TCMK-1 cells, while downregulation of FoxO3 promoted the inhibitory effect of TGF-β1 on the expression of Ptch1. Additionally, downregulation of Ptch1 increased TGF-β1-induced autophagy, as evidenced by an increase in the number of GFP-LC3 puncta and the increased protein expression of SOSTM1/p62 and LC3II/LC3I. Our findings showed that Ptch1 expression is negatively regulated by miR-342-5p and positively regulated by FoxO3, and downregulation of Ptch1 induced autophagy in TGF-β1-stimulated TCMK-1 cells. These findings will further our understanding of the molecular mechanisms of RF and provide useful novel therapeutic targets for RF.

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Section: Discussionsupporting

confidence: 58%

“…Autophagy mediates the development of RF, and a previous study showed that Ptch1 could inhibit autophagy in Hedgehog (Hh)-dependent cancers ( Chen et al, 2018 ). However, whether Ptch1 regulates autophagy and participates in the pathophysiological process of RF is not yet clear.…”

Section: Resultsmentioning

confidence: 99%

Regulation of Ptch1 by miR-342-5p and FoxO3 Induced Autophagy Involved in Renal Fibrosis

Tang

Wang

Xie

et al. 2020

Front. Bioeng. Biotechnol.

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“…These findings suggest that B7H3 degradation is mediated by autophagy. We further showed that the levels of autophagy-related markers, LC3B-II and p62 (Cohen-Kaplan et al, 2016;Chen et al, 2018) were significantly higher and lower, respectively in IDH1-R132H U87 cells when compared to the IDH1-WT cells (Figure 3E). Similarly, a parallel results of LC3B-II and p62 was also observed in IDH1-R132H U251 cells when compared to that in IDH1-WT cells (Figure 3F), which suggests an activated autophagy flux in IDH1-R132H U87 and U251 cells compared to IDH1-WT cells.…”

Section: Autophagy Inhibition Blocks B7h3 Degradationmentioning

confidence: 81%

The Inhibition of B7H3 by 2-HG Accumulation Is Associated With Downregulation of VEGFA in IDH Mutated Gliomas

Zhang

et al. 2021

Front. Cell Dev. Biol.

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B7H3 (also known as CD276) is a co-stimulator checkpoint protein of the cell surface B7 superfamily. Recently, the function beyond immune regulation of B7H3 has been widely studied. However, the expression preference and the regulation mechanism underlying B7H3 in different subtypes of gliomas is rarely understood. We show here that B7H3 expression is significantly decreased in IDH-mutated gliomas and in cultured IDH1-R132H glioma cells. Accumulation of 2-HG leads to a remarkable downregulation of B7H3 protein and the activity of IDH1-R132H mutant is responsible for B7H3 reduction in glioma cells. Inhibition of autophagy by inhibitors like leupeptin, chloroquine (CQ), and Bafilomycin A1 (Baf-A1) blocks the degradation of B7H3 in glioma cells. In the meantime, the autophagy flux is more active with higher LC3B-II and lower p62 in IDH1-R132H glioma cells than in IDH1-WT cells. Furthermore, sequence alignment analysis reveals potential LC3-interacting region (LIR) motifs “F-V-S/N-I/V” in B7H3. Moreover, B7H3 interacts with p62 and CQ treatment significantly enhances this interaction. Additionally, we find that B7H3 is positively correlated with VEGFA and MMP2 by bioinformatics analysis in gliomas. B7H3 and VEGFA are decreased in IDH-mutated gliomas and further reduced in 2-HGhigh gliomas compared to 2-HGlow glioma sections by IHC staining. Our study demonstrates that B7H3 is preferentially overexpressed in IDH wild-type gliomas and could serve as a potential theranostic target for the precise treatment of glioma patients with wild-type IDH.

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“…Pharmacologically, the use of GANT-61 enhances the cytotoxic effect of TMZ by the increment of acid vesicles and Beclin-1 expression ( 220 ). Furthermore, the regulatory domain of PTCH1, the main receptor of the Hedgehog pathway, interacts physically with the autophagy-related protein ATG101 in a nutrient starvation microenvironment, inhibiting the autophagic process ( 221 ). Additionally, GBM cells overexpressing the stem marker SOX3 showed an upregulation in Hh pathway activity and suppression of autophagy, leading to an increment in proliferation and invasion ( 222 ).…”

Section: Autophagy Activation As a Response To Internal Stimulimentioning

confidence: 99%

A Key Pathway to Cancer Resilience: The Role of Autophagy in Glioblastomas

et al. 2021

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There are no effective strategies for the successful treatment of glioblastomas (GBM). Current therapeutic modalities effectively target bulk tumor cells but leave behind marginal GBM cells that escape from the surgical margins and radiotherapy field, exhibiting high migratory phenotype and resistance to all available anti-glioma therapies. Drug resistance is mostly driven by tumor cell plasticity: a concept associated with reactivating transcriptional programs in response to adverse and dynamic conditions from the tumor microenvironment. Autophagy, or “self-eating”, pathway is an emerging target for cancer therapy and has been regarded as one of the key drivers of cell plasticity in response to energy demanding stress conditions. Many studies shed light on the importance of autophagy as an adaptive mechanism, protecting GBM cells from unfavorable conditions, while others recognize that autophagy can kill those cells by triggering a non-apoptotic cell death program, called ‘autophagy cell death’ (ACD). In this review, we carefully analyzed literature data and conclude that there is no clear evidence indicating the presence of ACD under pathophysiological settings in GBM disease. It seems to be exclusively induced by excessive (supra-physiological) stress signals, mostly from in vitro cell culture studies. Instead, pre-clinical and clinical data indicate that autophagy is an emblematic example of the ‘dark-side’ of a rescue pathway that contributes profoundly to a pro-tumoral adaptive response. From a standpoint of treating the real human disease, only combinatorial therapy targeting autophagy with cytotoxic drugs in the adjuvant setting for GBM patients, associated with the development of less toxic and more specific autophagy inhibitors, may inhibit adaptive response and enhance the sensibility of glioma cells to conventional therapies.

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Autophagic Flux Is Regulated by Interaction Between the C-terminal Domain of PATCHED1 and ATG101

Cited by 10 publications

References 33 publications

Regulation of Ptch1 by miR-342-5p and FoxO3 Induced Autophagy Involved in Renal Fibrosis

Regulation of Ptch1 by miR-342-5p and FoxO3 Induced Autophagy Involved in Renal Fibrosis

The Inhibition of B7H3 by 2-HG Accumulation Is Associated With Downregulation of VEGFA in IDH Mutated Gliomas

A Key Pathway to Cancer Resilience: The Role of Autophagy in Glioblastomas

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