ADAR1-mediated destabilization of INPP5J mRNA promotes PI3K/AKT/mTOR signal to inhibit autophagy in lung adenocarcinoma
- Cell Signal. 2026 Sep:145:112616. doi: 10.1016/j.cellsig.2026.112616.
- 1. Department of respiratory and critical care medicine, Respiratory Disease Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Fujian Provincial Sleep-disordered Breathing Clinic Center, China; Department of respiratory and critical care medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China; Department of Respiratory and Critical Care Medicine, Zhuzhou Central Hospital, Zhouzhu 412000, Hunan, China.
- 2. Department of Respiratory and Critical Care Medicine, Zhuzhou Central Hospital, Zhouzhu 412000, Hunan, China.
- 3. Department of respiratory and critical care medicine, Respiratory Disease Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Fujian Provincial Sleep-disordered Breathing Clinic Center, China; Department of respiratory and critical care medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China. Electronic address: [email protected].
Objective: The specific autophagic roles of Adenosine Deaminase RNA-specific 1 (ADAR) and inositol Polyphosphate-5-Phosphatase J (INPP5J) and their relationship in lung adenocarcinoma (LUAD) are poorly understood. This study sought to explore the involvement of ADAR and INPP5J in Autophagy and their functional interaction in LUAD.
Methods: Cancer tissues and the adjacent normal tissues from LUAD patients were obtained to analyze the expression of ADAR1 and Inositol Polyphosphate-5-Phosphatase J (INPP5J), as well as the autophagy-related PI3K/Akt/mTOR signal. LUAD cell (A549 and NCI-H1975) was treated with sh-ADAR1 alone or in combination with sh-INPP5J or 740 YP (a PI3K Activator) to investigate their effects on Autophagy. The binding between ADAR1 and INPP5J mRNA was determined by RIP-qPCR. Subsequently, A549 cells were subcutaneously injected into the nude mice, and sh-ADAR1 was administered with or without sh-INPP5J to explore their roles in tumor formation and Autophagy.
Results: Compared to the adjacent normal tissues, the mRNA level and the protein level of INPP5J expression were downregulated in Cancer tissues, while those of ADAR1 were upregulated. In LUAD patients, the ratios of p-PI3K/PI3K, p-AKT/Akt, p-mTOR/mTOR, and the level of p62 were elevated in Cancer tissues compared to the adjacent normal tissues, whereas LC3II/I and Beclin1 expression were reduced. Silencing ADAR1 downregulated the PI3K/Akt/mTOR pathway and p62 expression in LUAD cells, while upregulating LC3II/I and Beclin1 expression, but these effects were blocked by sh-INPP5J. Overexpression of INPP5J inhibited the PI3K/Akt/mTOR signaling pathway and p62 expression in LUAD cells, and upregulated LC3II/I and Beclin1 expression, but these effects were blocked by 740 YP. Silencing ADAR1 suppressed LUAD cell viability, colony formation, scratch healing, and tumor formation, but these effects were blocked by sh-INPP5J.
Conclusion: ADAR1 inhibits the LUAD-associated Autophagy by modifying INPP5J to activate the PI3K/Akt/mTOR pathway, providing a novel Adjuvant therapeutic target for LUAD.