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Cancer Res. 2017 Nov 1;77(21):5963-5976. doi: 10.1158/0008-5472.CAN-16-3313. Epub 2017 Sep 7.

Enhanced Acid Sphingomyelinase Activity Drives Immune Evasion and Tumor Growth in Non-Small Cell Lung Carcinoma.

Author information

1
Department of Molecular Pneumology, University Hospital, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
2
Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany.
3
Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany.
4
Department of Nephrology and Hypertension, University Hospital, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
5
Department of Psychiatry and Psychotherapy, University Hospital, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
6
Department of Thoracic Surgery, University Hospital, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
7
Institute of Pathology, University Hospital, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
8
Department of Molecular Pneumology, University Hospital, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. Susetta.Finotto@uk-erlangen.de.

Abstract

The lipid hydrolase enzyme acid sphingomyelinase (ASM) is required for the conversion of the lipid cell membrane component sphingomyelin into ceramide. In cancer cells, ASM-mediated ceramide production is important for apoptosis, cell proliferation, and immune modulation, highlighting ASM as a potential multimodal therapeutic target. In this study, we demonstrate elevated ASM activity in the lung tumor environment and blood serum of patients with non-small cell lung cancer (NSCLC). RNAi-mediated attenuation of SMPD1 in human NSCLC cells rendered them resistant to serum starvation-induced apoptosis. In a murine model of lung adenocarcinoma, ASM deficiency reduced tumor development in a manner associated with significant enhancement of Th1-mediated and cytotoxic T-cell-mediated antitumor immunity. Our findings indicate that targeting ASM in NSCLC can act by tumor cell-intrinsic and -extrinsic mechanisms to suppress tumor cell growth, most notably by enabling an effective antitumor immune response by the host. Cancer Res; 77(21); 5963-76. ©2017 AACR.

PMID:
28883000
DOI:
10.1158/0008-5472.CAN-16-3313
[Indexed for MEDLINE]
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