Interleukin-6 reverses Adriamycin resistance in nasal NK/T-cell lymphoma via downregulation of ABCC4 and inactivation of the JAK2/STAT3/NF-κB/P65 pathway.

Abstract

Chemotherapy is generally effective for extranodal natural killer (NK)/T-cell lymphoma (ENKTCL), nasal type. Nevertheless, multidrug resistance (MDR) remains a key challenge in treating nasal NK/T-cell lymphoma. Interleukin-6 (IL-6) is reportedly an important regulator of MDR in many cancers, implicating a role of IL-6 in the chemotherapy response. However, the effects and mechanism of IL-6 in nasal NK/T-cell lymphoma remain unclear. Herein, we demonstrated that the IL-6 serum level was decreased in nasal NK/T-cell lymphoma patients compared to chronic rhinitis patients. Lower serum levels of IL-6 were closely correlated with Ki67 expression and patient survival. ATP-binding cassette (ABC) drug transporter ABCC4 in patients was abnormally upregulated. IL-6 significantly inhibited resistance to Adriamycin (ADM) in ADM-resistant SNK-6 cells (SNK-6/ADM). Moreover, IL-6 resulted in cell cycle arrest and led to apoptosis in SNK-6/ADM cells. Furthermore, IL-6 decreased ABCC4, p-JAK2, p-STAT3, and phospho-NF-κB p65 expression in SNK-6/ADM cells. IL-6 in combination with ADM inhibited tumor growth and increased the survival of SNK-6/ADM xenograft mice. In conclusion, our findings suggest that IL-6 can inhibit the upregulation of ABCC4 and inactivate the JAK2/STAT3/NF-κB/P65 pathway to sensitize NK/T-cell lymphoma to ADM, indicating that combination therapy with IL-6 and other chemotherapeutic drugs may be effective in reversing acquired resistance in nasal NK/T-cell lymphoma.

• Authors: Ming Gao, Liying Liu, Xudong Zhang, Zhaoming Li, Mingzhi Zhang
• Journal: Environmental toxicology and pharmacology (Environ Toxicol Pharmacol) Vol. 85 Pg. 103639 (Jul 2021) ISSN: 1872-7077 [Electronic] Netherlands
• PMID: 33771682 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• ABCC4 protein, human
• Antibiotics, Antineoplastic
• IL6 protein, human
• Interleukin-6
• Multidrug Resistance-Associated Proteins
• STAT3 Transcription Factor
• STAT3 protein, human
• Transcription Factor RelA
• Doxorubicin
• JAK2 protein, human
• Janus Kinase 2

Topics

• Animals
• Antibiotics, Antineoplastic (pharmacology, therapeutic use)
• Cell Line, Tumor
• Chronic Disease
• Down-Regulation (drug effects)
• Doxorubicin (pharmacology, therapeutic use)
• Drug Resistance, Neoplasm (drug effects)
• Female
• Humans
• Interleukin-6 (blood, pharmacology, therapeutic use)
• Janus Kinase 2 (metabolism)
• Lymphoma, Extranodal NK-T-Cell (blood, drug therapy, metabolism)
• Male
• Mice, Inbred BALB C
• Mice, Nude
• Middle Aged
• Multidrug Resistance-Associated Proteins (metabolism)
• Rhinitis (blood, metabolism)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects)
• Transcription Factor RelA (metabolism)
• Mice