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.

journal_name

Oncol Rep

journal_title

Oncology reports

authors

Gao J,Qiu X,Xi G,Liu H,Zhang F,Lv T,Song Y

doi

10.3892/or.2018.6634

subject

Has Abstract

pub_date

2018-10-01 00:00:00

pages

1971-1984

issue

4

eissn

1021-335X

issn

1791-2431

journal_volume

40

pub_type

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