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Targeting GABARAPL1/HIF-2a axis to induce tumor cell apoptosis in nasopharyngeal carcinoma
Xiaopeng Huang1,2, Liya Zhou1,2, Jiawei Chen1
1Department of Radiation Oncology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province 570311, People's Republic of China.
Objectives:
The primary gene mutations associated with nasopharyngeal carcinoma (NPC) are located within the phosphoinositide 3-kinase-mammalian target of rapamycin signaling pathways, which have inhibitory effects on autophagy. Compounds that target autophagy could potentially be used to treat NPC. However, autophagy-related molecular targets in NPC remain to be elucidated. We aimed to examine levels of autophagy-related genes, including autophagy-related 4B cysteine peptidase (ATG4B) and gamma-aminobutyric acid (GABA) type A receptor-associated protein-like 1 (GABARAPL1), in NPC cells and explored their potential role as novel targets for the treatment of NPC.
Materials And Methods:
The mRNA and protein expression of autophagy-related genes were detected in several NPC cells. Levels of GABARAPL1 were modified by either overexpression or knockdown, followed by examining downstream targets using RT-qPCR and western blotting. The role of GABARAPL1 in NPC proliferation and apoptosis was examined by flow cytometry. Furthermore, the role of GABARAPL1 was assessed in vivo using a nude mouse xenograft tumor model. The underlying mechanism by which GABARAPL1 regulated nasopharyngeal tumor growth was investigated.
Results:
Autophagy-related 4B cysteine peptidase (ATG4B), GABARAPL1, and Unc-51-like kinase 1 (ULK1) were significantly down-regulated in multiple NPC cell lines. Overexpression of GABARAPL1 up-regulated the expression of autophagy-related proteins, decreased the level of hypoxia-inducible factor (HIF)-2α, and induced apoptosis in NPC cells. Importantly, overexpression of GABARAPL1 slowed tumor growth. Western blotting showed that autophagy was activated, and HIF-2α was down-regulated in tumor tissues.
Conclusion:
HIF-2α, as a substrate for autophagic degradation, may play an interesting role during NPC progression.
Insights
This study reveals that gamma-aminobutyric acid (GABA) type A receptor-associated protein-like 1 (GABARAPL1) is down-regulated in nasopharyngeal carcinoma (NPC). Restoring GABARAPL1 levels inhibits NPC growth and induces apoptosis, suggesting its potential as a therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Nasopharyngeal carcinoma (NPC) is associated with mutations in PI3K-mTOR pathways, impacting autophagy.
- Targeting autophagy presents a potential therapeutic strategy for NPC, but specific molecular targets require identification.
- Autophagy-related genes, such as ATG4B and GABARAPL1, are implicated in cancer progression.
Purpose of the Study:
- To investigate the expression levels of autophagy-related genes, specifically ATG4B and GABARAPL1, in NPC cells.
- To explore the potential of GABARAPL1 as a novel therapeutic target for nasopharyngeal carcinoma treatment.
- To elucidate the mechanism by which GABARAPL1 influences nasopharyngeal tumor growth.
Main Methods:
- Detected mRNA and protein expression of autophagy-related genes in NPC cell lines.
- Manipulated GABARAPL1 levels via overexpression and knockdown, assessing downstream targets with RT-qPCR and western blotting.
- Evaluated NPC cell proliferation and apoptosis using flow cytometry and assessed tumor growth in vivo using a nude mouse xenograft model.
Main Results:
- ATG4B, GABARAPL1, and ULK1 were significantly downregulated in multiple NPC cell lines.
- GABARAPL1 overexpression upregulated autophagy-related proteins, decreased HIF-2α levels, and induced apoptosis in NPC cells.
- Overexpression of GABARAPL1 significantly slowed tumor growth, with activated autophagy and downregulated HIF-2α observed in tumor tissues.
Conclusions:
- GABARAPL1 plays a crucial role in regulating NPC cell proliferation and apoptosis.
- The study identifies GABARAPL1 as a potential therapeutic target for nasopharyngeal carcinoma.
- Hypoxia-inducible factor 2-alpha (HIF-2α) may be involved in NPC progression as a substrate for autophagic degradation.
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