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Autophagy and Glycometabolic Reprograming in the Malignant Progression of Lung Cancer: A Review.

ABSTRACT: Lung cancer is one of the leading causes of cancer-related deaths worldwide. However, there are currently limited treatment options that are widely available to patients with advanced lung cancer, and further research is required to inhibit or reverse disease progression more effectively. In lung and other solid tumor cancers, autophagy and glycometabolic reprograming are critical regulators of malignant development, including proliferation, drug resistance, invasion, and metastasis. To provide a theoretical basis for therapeutic strategies targeting autophagy and glycometabolic reprograming to prevent lung cancer, we review how autophagy and glycometabolism are regulated in the malignant development of lung cancer based on research progress in other solid tumors.

SUBMITTER: Li Y

PROVIDER: S-EPMC10467373 | biostudies-literature | 2023 Jan-Dec

REPOSITORIES: biostudies-literature

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Autophagy and Glycometabolic Reprograming in the Malignant Progression of Lung Cancer: A Review.

Li Yuting Y Liu Tongzuo T Wang Xiaoqun X Jia Yingjie Y Cui Huantian H

Technology in cancer research & treatment 20230101

Lung cancer is one of the leading causes of cancer-related deaths worldwide. However, there are currently limited treatment options that are widely available to patients with advanced lung cancer, and further research is required to inhibit or reverse disease progression more effectively. In lung and other solid tumor cancers, autophagy and glycometabolic reprograming are critical regulators of malignant development, including proliferation, drug resistance, invasion, and metastasis. To provide ...[more]

PMID: 37605558

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Project description:BackgroundLung cancer poses a serious threat to human health, but its molecular mechanisms remain unclear. Circular RNAs (circRNAs) are closely associated with tumour progression, and the important role of 8-oxoguanine (o8G) modification in regulating the fate of RNA has been gradually revealed. However, o8G modification of circRNAs has not been reported. We identified circPLCE1, which is significantly downregulated in lung cancer, and further investigated the o8G modification of circPLCE1 and the related mechanism in lung cancer progression.MethodsWe identified differentially expressed circRNAs by RNA high-throughput sequencing and then conducted methylated RNA immunoprecipitation (MeRIP), immunofluorescence (IF) analysis, crosslinking immunoprecipitation (CLIP) and actinomycin D (ActD) assays to explore circPLCE1 o8G modification. The biological functions of circPLCE1 in vivo and in vitro were clarified via establishing a circPLCE1 silencing/overexpression system. Tagged RNA affinity purification (TRAP), RNA Immunoprecipitation (RIP) and coimmunoprecipitation (Co-IP) assays, and pSIN-PAmCherry-KFERQ-NE reporter gene were used to elucidate the molecular mechanism by which circPLCE1 inhibits lung cancer progression.ResultsThis study revealed that reactive oxygen species (ROS) can induce circPLCE1 o8G modification and that AUF1 can mediate a decrease in circPLCE1 stability. We found that circPLCE1 significantly inhibited lung cancer progression in vitro and in vivo and that its expression was associated with tumour stage and prognosis. The molecular mechanism was elucidated: circPLCE1 targets the HSC70 protein, increases its ubiquitination level, regulates ATG5-dependent macroautophagy via the chaperone-mediated autophagy (CMA) pathway, and ultimately inhibits lung cancer progression.Conclusiono8G-modified circPLCE1 inhibits lung cancer progression through CMA to inhibit macroautophagy and alter cell fate. This study provides not only a new theoretical basis for elucidating the molecular mechanism of lung cancer progression but also potential targets for lung cancer treatment.

Project description:Rationale: Lung cancer remains a major global health burden with limited therapeutic options. Alternative splicing, a critical post-transcriptional process, contributes to lung cancer progression through autophagy, although the underlying mechanisms remain largely unexplored. This study aims to elucidate the role of DDX24 as a splicing factor that contributes to lung cancer progression via autophagy. Methods: To establish the link between DDX24 and lung cancer progression, we performed colony formation assays, growth curve analyses, and xenograft tumor models in nude mice. Mass spectrometry and RNA sequencing were employed to investigate the involvement of DDX24 in alternative splicing, with a specific focus on the splicing of IKBKG. The mechanisms by which DDX24 regulates autophagy were further explored using co-immunoprecipitation and luciferase reporter assays. Results: The splicing factor DDX24 is significantly elevated in lung cancer tissues. Loss of DDX24 suppresses lung cancer growth by promoting autophagy. We identified DDX24 as a splicing factor that plays critical roles in the regulation of alternative splicing. Mechanistically, DDX24 regulates the alternative splicing of autophagy-related genes, including IKBKG. We demonstrate that DDX24 directly binds to IKBKG pre-mRNA, whereas DDX24 ablation stimulates the generation of the long splicing isoform of IKBKG, thereby promoting autophagy through activating of the NF-kB signaling pathway and the transcription of the BECN1 gene. Functional rescue experiments confirm that the long IKBKG isoform-mediated autophagy confers the anti-tumor effects of DDX24 depletion. In addition, IKBKG-L is positively associated with improved survival in lung cancer patients. Conclusions: This study uncovers a novel regulatory axis involving DDX24, IKBKG splicing, and autophagy in lung cancer. Our findings suggest that targeting DDX24 may represent a promising therapeutic strategy for lung cancer treatment, offering new insights into the molecular underpinnings of this disease.

Dataset Information

Autophagy and Glycometabolic Reprograming in the Malignant Progression of Lung Cancer: A Review.

Publications

Autophagy and Glycometabolic Reprograming in the Malignant Progression of Lung Cancer: A Review.

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