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PANX2 Suppresses Lung Adenocarcinoma Progression by Inducing Disulfidptosis and Enhancing Antitumor Immunity
Yi Chen1,2, Zhao-Yu Liu1, Gao-Wen Qu1
1Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
Abstract:
Lung adenocarcinoma (LUAD) remains a leading cause of cancer mortality with limited therapeutic options. Disulfidptosis, a novel cell death modality driven by disulfide stress, represents a promising target, yet its regulation in LUAD is poorly defined. Here, we identify Pannexin 2 (PANX2) as a tumor suppressor in LUAD. Clinically, PANX2 expression is downregulated during tumor progression, and low PANX2 levels correlate with poor prognosis. Functionally, PANX2 overexpression induces disulfidptosis in LUAD cells through two convergent axes: (i) activating NRF2 via Ca2 +-dependent stabilization and nuclear translocation to upregulate SLC7A11, increasing cystine uptake and NADPH consumption; (ii) suppressing G6PD to impair NADPH regeneration, compromising cystine clearance. This dual regulation synergistically depletes NADPH, causes cystine overload, and triggers disulfide crosslinking of cytoskeletal proteins, leading to actin cytoskeleton collapse. Moreover, PANX2 enhances extracellular ATP release, activating P2X7R signaling on immune cells to promote antitumor immune infiltration. In humanized mouse models, PANX2 overexpression suppresses tumor growth-effects reversed by NRF2 knockdown, G6PD overexpression, or P2X7R blockade. Collectively, our findings establish PANX2 as a tumor suppressor linking disulfidptosis to antitumor immunity, offering a dual-target strategy for LUAD therapy.
Insights
Pannexin 2 (PANX2) acts as a tumor suppressor in lung adenocarcinoma (LUAD) by inducing disulfidptosis and enhancing antitumor immunity. Its downregulation correlates with poor prognosis, suggesting therapeutic potential.
Area of Science:
- Oncology
- Cell Biology
- Immunology
Background:
- Lung adenocarcinoma (LUAD) has limited treatment options.
- Disulfidptosis, a cell death pathway triggered by disulfide stress, is a potential therapeutic target in LUAD.
- The regulation of disulfidptosis in LUAD is not well understood.
Purpose of the Study:
- To identify novel tumor suppressors in LUAD.
- To elucidate the role of Pannexin 2 (PANX2) in LUAD progression and its underlying molecular mechanisms.
- To explore the potential of targeting PANX2 for LUAD therapy.
Main Methods:
- Analysis of clinical LUAD data to correlate PANX2 expression with prognosis.
- In vitro studies using LUAD cell lines to investigate PANX2 function.
- Biochemical assays to determine the molecular pathways regulated by PANX2, including NRF2, SLC7A11, G6PD, and NADPH metabolism.
- Assessment of extracellular ATP release and P2X7R signaling.
- In vivo studies using humanized mouse models to evaluate the therapeutic efficacy of PANX2 overexpression.
Main Results:
- PANX2 is downregulated in LUAD during tumor progression, and low expression predicts poor prognosis.
- PANX2 overexpression induces disulfidptosis by activating NRF2 and suppressing G6PD, leading to NADPH depletion and cystine overload.
- PANX2 promotes antitumor immunity through extracellular ATP release and P2X7R activation.
- PANX2 overexpression suppresses tumor growth in mouse models, an effect dependent on NRF2, G6PD, and P2X7R.
Conclusions:
- PANX2 functions as a tumor suppressor in LUAD.
- PANX2 links disulfidptosis induction to the enhancement of antitumor immunity.
- Targeting PANX2 offers a dual therapeutic strategy for LUAD by inducing cell death and boosting immune response.
