Downregulation of GSDMD attenuates tumor proliferation via the intrinsic mitochondrial apoptotic pathway and inhibition of EGFR/Akt signaling and predicts a good prognosis in non‑small cell lung cancer.

Abstract

Gasdermin D (GSDMD) is a newly discovered pyroptosis executive protein, which can be cleaved by inflammatory caspases and is essential for secretion of IL‑1β, making it a critical mediator of inflammation. However, the precise role of GSDMD in carcinogenesis remains nearly unknown. Considering the vital role of inflammation in tumorigenesis, we investigated the biological function of GSDMD in non‑small cell lung cancer (NSCLC). Our study demonstrated that the GSDMD protein levels were significantly upregulated in NSCLC compared to these levels in matched adjacent tumor specimens. Higher GSDMD expression was associated with aggressive traits including larger tumor size and more advanced tumor-node-metastasis (TNM) stages. In addition, high GSDMD expression indicated a poor prognosis in lung adenocarcinoma (LUAD), but not in squamous cell carcinoma (LUSC). Knockdown of GSDMD restricted tumor growth in vitro and in vivo. Notably, intrinsic and extrinsic activation of pyroptotic (NLRP3/caspase‑1) signaling in GSDMD‑deficient tumor cells induced another type of programmed cell death (apoptosis), instead of pyroptosis. GSDMD depletion activated the cleavage of caspase‑3 and PARP, and promoted cancer cell death via intrinsic mitochondrial apoptotic pathways. In addition, co‑expression analyses indicated a correlation between GSDMD and EGFR/Akt signaling. Collectively, our results revealed a crosstalk between pyroptotic signaling and apoptosis in tumor cells. Knockdown of GSDMD attenuated tumor proliferation by promoting apoptosis and inhibiting EGFR/Akt signaling in NSCLC. In conclution, GSDMD is an independent prognostic biomarker for LUAD.

• Authors: Jianwei Gao, Xiangyu Qiu, Guangmin Xi, Hongbing Liu, Fang Zhang, Tangfeng Lv, Yong Song
• Journal: Oncology reports (Oncol Rep) Vol. 40 Issue 4 Pg. 1971-1984 (Oct 2018) ISSN: 1791-2431 [Electronic] Greece
• PMID: 30106450 (Publication Type: Journal Article)

Chemical References

• Apoptosis Regulatory Proteins
• Biomarkers, Tumor
• GSDMD protein, human
• Intracellular Signaling Peptides and Proteins
• Neoplasm Proteins
• Phosphate-Binding Proteins
• EGFR protein, human
• ErbB Receptors
• AKT1 protein, human
• Proto-Oncogene Proteins c-akt
• Caspases

Topics

• Adenocarcinoma (metabolism, secondary, therapy)
• Animals
• Apoptosis
• Apoptosis Regulatory Proteins (metabolism)
• Biomarkers, Tumor (metabolism)
• Carcinoma, Non-Small-Cell Lung (metabolism, secondary, therapy)
• Carcinoma, Squamous Cell (metabolism, secondary, therapy)
• Case-Control Studies
• Caspases (metabolism)
• Cell Movement
• Cell Proliferation
• ErbB Receptors (genetics, metabolism)
• Female
• Follow-Up Studies
• Gene Expression Regulation, Neoplastic
• Humans
• Intracellular Signaling Peptides and Proteins
• Lung Neoplasms (metabolism, pathology, therapy)
• Lymphatic Metastasis
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mitochondria (metabolism, pathology)
• Neoplasm Proteins (genetics, metabolism)
• Phosphate-Binding Proteins
• Prognosis
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Signal Transduction
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays