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Pharmacological inhibition of caspase-8 limits lung tumour outgrowth
Michela Terlizzi1, Vincenzo Giuseppe Di Crescenzo2, Giuseppe Perillo3
1Department of Pharmacy, University of Salerno, Fisciano, Italy.
Background And Purpose:
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.
Experimental Approach:
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.
Key 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 And Implications:
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.
Insights
Caspase-8 inhibition reduces lung cancer growth by decreasing inflammation and myeloid-derived suppressor cells. The short segment of c-FLIP dictates whether caspase-8 promotes tumor proliferation or regression.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Lung cancer remains a leading cause of cancer mortality globally.
- Conventional therapies face challenges with chemotherapy resistance.
- Caspase-8 is implicated in cell death and serves as a prognostic marker in lung cancer.
Purpose of the Study:
- To investigate the role of caspase-8 in lung carcinoma.
- To understand the mechanisms underlying caspase-8's function in lung cancer progression.
Main Methods:
- Utilized human non-small cell lung cancer (NSCLC) samples.
- Employed a mouse model of carcinogen-induced lung cancer.
- Pharmacologically inhibited caspase-8 using z-IETD-FMK.
Main Results:
- Active caspase-8 levels were similar in healthy and cancerous NSCLC tissues and in tumor-bearing mice.
- Caspase-8 inhibition reduced tumor outgrowth, pro-inflammatory cytokine release (IL-6, TNF-α, IL-18, IL-1α, IL-33), and myeloid-derived suppressor cell recruitment.
- Apoptotic pathways were not activated; instead, increased levels of the short segment of c-FLIP (c-FLIPs) were observed upon caspase-8 inhibition.
- Higher c-FLIPs levels were detected in healthy human lung samples compared to cancerous ones.
Conclusions:
- Caspase-8 is a key regulator of cancer-associated inflammation in lung carcinoma.
- The presence of c-FLIPs determines whether caspase-8 activity leads to tumor proliferation or regression.
- Targeting caspase-8, potentially in conjunction with modulating c-FLIPs, could offer novel therapeutic strategies for lung cancer.
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