Pharmacological inhibition of caspase-8 limits lung tumour outgrowth.
OBJECTIVE
Lung cancer is one of the leading causes of cancer death worldwide. Despite advances in therapy, conventional therapy is still the main treatment and has a high risk of chemotherapy resistance. Caspase-8 is involved in cell death and is a recognized marker for poor patient prognosis.


METHODS
To elucidate the role of caspase-8 in lung carcinoma, we used human samples of non-small cell lung cancer (NSCLC) and a mouse model of carcinogen-induced lung cancer.


RESULTS
Healthy and cancerous NSCLC samples had similar levels of the active form of caspase-8. Similarly, lung tumour-bearing mice had high levels of the active form of caspase-8. Pharmacological inhibition of caspase-8 by z-IETD-FMK robustly reduced tumour outgrowth and this was closely associated with a reduction in the release of pro-inflammatory cytokines, IL-6, TNF-α, IL-18, IL-1α, IL-33, but not IL-1β. Furthermore, inhibition of caspase-8 reduced the recruitment of innate suppressive cells, such as myeloid-derived suppressor cells, but not of regulatory T cells to lungs of tumour-bearing mice. However, despite the well-known role of caspase-8 in cell death, the apoptotic cascade (caspase-3, caspase-9 and Bcl-2 dependent) was not active in lungs of z-IETD-treated tumour-bearing mice, but instead higher levels of the short segment of c-FLIP (c-FLIPs) were detected. Similarly, human healthy lung samples had higher levels of c-FLIPs than cancerous samples.


CONCLUSIONS
Our data suggest that caspase-8 is an important orchestrator of cancer-associated inflammation and the presence of short segment of c-FLIP determines whether caspase-8 induces tumour proliferation or tumour arrest/regression in the lung.
Department of Pharmacy, University of Salerno, Fisciano, Italy.
Michela
M
Terlizzi
Department of Medicine and Surgery, University of Salerno, Fisciano, Italy.
Vincenzo Giuseppe
VG
Di Crescenzo
Struttura Complessa di Malattie dell'Apparato Respiratorio, A.O.U. San Giovanni di Dio e Ruggi D'Aragona, Salerno, Italy.
Giuseppe
G
Perillo
Endoscopia Bronchiale e Pneumologia Interventistica, A.O.U. San Giovanni di Dio e Ruggi D'Aragona, Salerno, Italy.
Antonio
A
Galderisi
Department of Pharmacy, University of Salerno, Fisciano, Italy.
Aldo
A
Pinto
Department of Pharmacy, University of Salerno, Fisciano, Italy.
Rosalinda
R
Sorrentino
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D053181:Caspase 8 / Q000378:metabolism*; D061945:Caspase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D022423:Myeloid Cells / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects
D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D061945:Caspase Inhibitors; D018836:Inflammation Mediators; D009842:Oligopeptides; C403753:benzyloxycarbonyl-isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone; D053181:Caspase 8