S1P-Induced TNF-α and IL-6 Release from PBMCs Exacerbates Lung Cancer-Associated Inflammation

Terlizzi, Michela; Colarusso, Chiara; Somma, Pasquale; Rosa, Ilaria De; Panico, Luigi; Pinto, Aldo; Sorrentino, Rosalinda

doi:10.3390/cells11162524

Cited by 12 publications

(18 citation statements)

References 29 publications

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“…Sphingosine levels showed a similar trend, although its levels were much lower than S1P (H S1P median: 131.059 nM vs. H sphingosine median: 0.3215 nM, p < 0.0001; ADK S1P median: 86.629 nM vs. ADK sphingosine median: 0.251 nM, p < 0.0001; SCC S1P median: 108.148 nM vs. SCC sphingosine median: 0.522 nM, p < 0.0001) ( Supplementary Figure S1B ). Because we already demonstrated that lung cancer epithelial cells synthetize and release high levels of S1P [ 19 ], and that circulating S1P acts on its receptors both on lung cancer tissues [ 3 , 19 ] and circulating cells [ 32 ], these data may imply either that S1P from the plasma is driven toward receptors in the case of ADK patients, or that a compromised or non-relevant S1P metabolism/synthesis occurs in the SCC histotype.…”

Section: Resultsmentioning

confidence: 99%

“…The synthesis of ceramides into sphingosine and S1P is prompted by the activation of the ceramidases (ASAH1 and 2, ACER1, 2 and 3) ( Figure 4 A, orange squares). ASAH1 is the most studied ceramidase; we have demonstrated its involvement in lung cancer [ 3 , 18 , 19 , 32 ]. According to the RNAseq database (TCGA_LUSC_2016), male and female non-cancerous lung tissues expressed similar levels of mRNA ASAH1 ( Figure 5 A; male mean expression: 1.72 vs. female mean: 1.737; p = 0.53).…”

Section: Resultsmentioning

confidence: 99%

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Sex Differences in Sphingosine-1-Phosphate Levels Are Dependent on Ceramide Synthase 1 and Ceramidase in Lung Physiology and Tumor Conditions

Terlizzi

Colarusso

Ferraro

et al. 2023

IJMS

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Sex is a biological variable that can reflect clinical outcomes in terms of quality of life, therapy effectiveness, responsiveness and/or toxicity. Sphingosine-1-phosphate (S1P) is a lipidic mediator whose activity can be influenced by sex. To evaluate whether the S1P axis underlies sex ‘instructions’ in the lung during physiological and oncological lung conditions, sphingosine and S1P were quantified in the blood of healthy (H) volunteers, lung adenocarcinoma (ADK) and squamous cell carcinoma (SCC) patients of both sexes. S1P receptors and their metabolic enzymes were evaluated in the tissues. Circulating levels of S1P were similar among H female and male subjects and female SCC patients. Instead, male and female ADK patients had lower circulating S1P levels. S1P receptor 3 (S1PR3) was physiologically expressed in the lung, but it was overexpressed in male SCC, and female and male ADK, but not in female SCC patients, who showed a significantly reduced ceramide synthase 1 (CERS1) mRNA and an overexpression of the ceramidase (ASAH1) precursor in lung tumor tissues, compared to male SCC and both male and female ADK patients. These findings highlighted sex differences in S1P rheostat in pathological conditions, but not in physiological conditions, identifying S1P as a prognostic mediator depending on lung cancer histotype.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Sex Differences in Sphingosine-1-Phosphate Levels Are Dependent on Ceramide Synthase 1 and Ceramidase in Lung Physiology and Tumor Conditions

Terlizzi

Colarusso

Ferraro

et al. 2023

IJMS

Self Cite

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“…In lung cancer, high expression of S1P increases the release of TNF-α and IL-6 from PBMC of lung cancer origin. Compared to the SPHK2 inhibitor Opaganib, which only reduces the release of IL-6 from PBMC of lung cancer origin, inhibition of SPHK1 by PF543 can down-regulate both TNF-α and IL-6 release and more effectively inhibit lung cancer progression [45]. The SPHK1-specific inhibitor SKI-II has also been reported to specifically inhibit the growth of human acute myeloid leukemia cells in vitro while being safe for PBMC from healthy donors.…”

Section: Discussionmentioning

confidence: 99%

HOXC11 drives lung adenocarcinoma progression through transcriptional regulation of SPHK1

Peng

Liu

et al. 2023

Cell Death Dis

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Lung adenocarcinoma (LUAD) is a fatal threat to human health, while the mechanism remains unclear, and the therapy brings limited therapeutic effects. Transcription factor Homeobox C11 (HOXC11) was previously proved to be related to hind limbs and metanephric development during the embryonic phase, and its role in tumors has been gradually recognized. Our study found that HOXC11 overexpressed in LUAD and was associated with worse overall survival. Moreover, its expression in lung cancer was regulated by IκB kinase α (IKKα), a pivotal kinase in NF-κB signaling, which was related to the ubiquitination of HOXC11. We further proved that HOXC11 could enhance the ability of proliferation, migration, invasion, colony formation, and the progression of the cell cycle in LUAD cells. Meanwhile, it also accelerated the formation of subcutaneous and lung metastases tumors. In contrast, loss of HOXC11 in LUAD cells significantly inhibited these malignant phenotypes. At the same time, HOXC11 regulated the expression of sphingosine kinase 1 (SPHK1) by directly binding to its promoter region. Therefore, we conclude that HOXC11 impacts the development of LUAD and facilitates lung cancer progression by promoting the expression of SPHK1.

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“…Sphingolipid signaling was linked to TME modifications and resistance of cancer cells to NK cell-based elimination [ 267 ]. For instance, S1P-stimulated lung cancer-derived monocytes secreted TNF-α and IL-6 in S1P receptor 3 (S1P3)/mTOR/K-Ras-dependent manner, while NF-κB was not implicated [ 268 ]. The authors suggested that greater presence of S1P within the TME of lung cancer may orchestrate tumorigenic immune responses [ 268 ].…”

Section: Sphingolipids As Mediators Facilitators and Inhibitors Of Tn...mentioning

confidence: 99%

“…For instance, S1P-stimulated lung cancer-derived monocytes secreted TNF-α and IL-6 in S1P receptor 3 (S1P3)/mTOR/K-Ras-dependent manner, while NF-κB was not implicated [ 268 ]. The authors suggested that greater presence of S1P within the TME of lung cancer may orchestrate tumorigenic immune responses [ 268 ]. However, this statement requires experimental confirmation, as the exact mechanisms (specific S1P targets) of this effect remain unclear and/or controversial [ 269 , 270 ].…”

Section: Sphingolipids As Mediators Facilitators and Inhibitors Of Tn...mentioning

confidence: 99%

Signaling controversy and future therapeutical perspectives of targeting sphingolipid network in cancer immune editing and resistance to tumor necrosis factor-α immunotherapy

Sukocheva,

Neganova,

Aleksandrova

et al. 2024

Cell Commun Signal

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Anticancer immune surveillance and immunotherapies trigger activation of cytotoxic cytokine signaling, including tumor necrosis factor-α (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL) pathways. The pro-inflammatory cytokine TNF-α may be secreted by stromal cells, tumor-associated macrophages, and by cancer cells, indicating a prominent role in the tumor microenvironment (TME). However, tumors manage to adapt, escape immune surveillance, and ultimately develop resistance to the cytotoxic effects of TNF-α. The mechanisms by which cancer cells evade host immunity is a central topic of current cancer research. Resistance to TNF-α is mediated by diverse molecular mechanisms, such as mutation or downregulation of TNF/TRAIL receptors, as well as activation of anti-apoptotic enzymes and transcription factors. TNF-α signaling is also mediated by sphingosine kinases (SphK1 and SphK2), which are responsible for synthesis of the growth-stimulating phospholipid, sphingosine-1-phosphate (S1P). Multiple studies have demonstrated the crucial role of S1P and its transmembrane receptors (S1PR) in both the regulation of inflammatory responses and progression of cancer. Considering that the SphK/S1P/S1PR axis mediates cancer resistance, this sphingolipid signaling pathway is of mechanistic significance when considering immunotherapy-resistant malignancies. However, the exact mechanism by which sphingolipids contribute to the evasion of immune surveillance and abrogation of TNF-α-induced apoptosis remains largely unclear. This study reviews mechanisms of TNF-α-resistance in cancer cells, with emphasis on the pro-survival and immunomodulatory effects of sphingolipids. Inhibition of SphK/S1P-linked pro-survival branch may facilitate reactivation of the pro-apoptotic TNF superfamily effects, although the role of SphK/S1P inhibitors in the regulation of the TME and lymphocyte trafficking should be thoroughly assessed in future studies.

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S1P-Induced TNF-α and IL-6 Release from PBMCs Exacerbates Lung Cancer-Associated Inflammation

Cited by 12 publications

References 29 publications

Sex Differences in Sphingosine-1-Phosphate Levels Are Dependent on Ceramide Synthase 1 and Ceramidase in Lung Physiology and Tumor Conditions

Sex Differences in Sphingosine-1-Phosphate Levels Are Dependent on Ceramide Synthase 1 and Ceramidase in Lung Physiology and Tumor Conditions

HOXC11 drives lung adenocarcinoma progression through transcriptional regulation of SPHK1

Signaling controversy and future therapeutical perspectives of targeting sphingolipid network in cancer immune editing and resistance to tumor necrosis factor-α immunotherapy

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