Cytokines from the tumor microenvironment modulate sirtinol cytotoxicity in A549 lung carcinoma cells

Autor: Bhavani S. Shankar, Shyama Pal, Krishna B. Sainis
Rok vydání: 2013
Předmět:
Programmed cell death
Lung Neoplasms
Paclitaxel
Cell Survival
Necroptosis
medicine.medical_treatment
Immunology
Apoptosis
Naphthols
Biochemistry
Receptors
Tumor Necrosis Factor
Receptor
IGF Type 1
TNF-Related Apoptosis-Inducing Ligand
Phosphatidylinositol 3-Kinases
Sirtuin 1
Transforming Growth Factor beta
Cell Line
Tumor
medicine
Tumor Microenvironment
Immunology and Allergy
Humans
Epidermal growth factor receptor
Molecular Targeted Therapy
Insulin-Like Growth Factor I
Molecular Biology
Caspase
Janus Kinases
Tumor microenvironment
biology
Tumor Necrosis Factor-alpha
Growth factor
Hematology
Tyrphostins
Cell biology
ErbB Receptors
Receptors
TNF-Related Apoptosis-Inducing Ligand
Drug Resistance
Neoplasm
Benzamides
biology.protein
Cancer research
Cytokines
Cisplatin
Janus kinase
Transforming growth factor
Zdroj: Cytokine. 64(1)
ISSN: 1096-0023
Popis: Cytokines in tumor microenvironment play an important role in the success or failure of molecular targeted therapies. We have chosen tumor necrosis factor α (TNF-α), TNF related apoptosis inducing ligand (TRAIL), insulin-like growth factor 1 (IGF-1) and transforming growth factor β (TGF-β) as representative pro-inflammatory, pro-apoptotic, anti-apoptotic and anti-inflammatory tumor derived cytokines. Analysis of Oncomine database revealed the differential expression of these cytokines in a subset of cancer patients. The effects of these cytokines on cytotoxicity of FDA approved drugs - cisplatin and taxol and inhibitors of epidermal growth factor receptor - AG658, Janus kinase - AG490 and SIRT1 - sirtinol were assessed in A549 lung cancer cells. TRAIL augmented cytotoxicity of sirtinol and IGF-1 had a sparing effect. Since TRAIL and IGF-1 differentially modulated sirtinol cytotoxicity, further studies were carried out to identify the mechanisms. Sirtinol or knockdown of SIRT1 increased the expression of death receptors DR4 and DR5 and sensitized A549 cells to TRAIL. Increased cell death in presence of TRAIL and sirtinol was caspase independent and demonstrated classical features of necroptosis. Inhibition of iNOS increased caspase activity and switched the mode of cell death to caspase mediated apoptosis. Interestingly, sirtinol or SIRT1 knockdown did not increase IGF-1R expression. Instead, it abrogated ligand induced downregulation of IGF-1R and increased cell survival through PI3K-AKT pathway. In conclusion, these findings reveal that the tumor microenvironment contributes to modulation of cytotoxicity of drugs and that combination therapy, with agents that increase TRAIL signaling and suppress IGF-1 pathway may potentiate anticancer effect.
Databáze: OpenAIRE
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