Affiliation:
1. Harbin Medical University Cancer Hospital
2. Sichuan Cancer Hospital
3. Heilongjiang Provincial Hospital
Abstract
Abstract
Background: Mammalian apurinic/apyrimidinic endonuclease 1 (APE1, APEX1) is a multifunctional enzyme that maintains cell homeostasis. It is involved in the base excision repair (BER) pathway and plays a key role in radiation-induced DNA damage response. Nevertheless, the relationship between APE1-driven radiation resistance and pyroptosis in lung adenocarcinoma (LUAD) cells and the underlying molecular mechanisms remain unclear.
Methods: The up-regulated expression gene APE1 that was screened out through differential expression analysis of biogenic data and RNA-seq results. The q-PCR experiments and immunohistochemical these two techniques were used to detect its expression both in lung adenocarcinoma and normal lung tissues. The effect of APE1 on the proliferation was determined by two experiments as CCK-8 and EdU. The Transwell and scratch tests were both used to evaluate the invasion and migration ability. The effect of APE1 on DNA damage and radiotherapy sensitivity was determined by clonal formation, immunofluorescence and flow cytometry. Through biogenic analysis and enrichment of APE1 related molecules and pathways, the regulation of APE1 on STING and its downstream signaling pathways was verified by western blot. In addition, APE1 directly interacts with AIM2 and DDX41 detected by RNA-seq and co-immunoprecipitation to inactivate the interferon gene stimulating factor (STING) pathway, thereby inhibiting pyroptosis after radiotherapy. The effect of APE1 on tumor occurrence and radiotherapy in vivo was observed in nude mouse model.
Results: The expression level of APE1 was significantly increased in LUAD and can promote the activity levels of proliferation, migration and invasion in LUAD cells. APE1 plays an anti-radiation role by regulating STING pathway through DDX41. APE1 can induce pyroptosis of cells after radiotherapy through AIM2; APE1 can promote tumor generation, enhance tumor load and inhibit radiosensitivity in vivo.
Conclusions: APE1 protects LUAD cells against radiation-induced damage and induces radio-resistance by targeting the STING pathway. could induce pyroptosis and negatively regulate by interaction with AIM2 and DDX41. APE1 inhibitors should be considered for enhancing the radiosensitivity of LUAD cells and improving patient prognosis and therapeutic outcomes. Thus, APE1 may play a role in affecting tumor immune microenvironment and tumor immunotherapy.
Publisher
Research Square Platform LLC
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