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

https://doi.org/10.1016/j.etap.2021.103639Get rights and content

Highlights

  • Lower IL-6 was closely correlated with patient survival.

  • ABCC4 in patients was abnormally upregulated.

  • IL-6 significantly inhibited resistance to ADM of SNK-6/ADM.

  • IL-6 inhibits ABCC4 and inactivates the JAK2/STAT3/NF-κB/P65 pathway.

  • IL-6 reverses ADM resistance of extranodal natural killer T-cell lymphoma

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.

Introduction

Natural killer/T-cell lymphoma (NKTCL) is a non-Hodgkin’s malignancy characterized clinically by aggressive, unrelenting destruction of the midline structures of the nasal fossa and palate (Tse and Kwong, 2017). ENKTCL is always found only in the area around the nose (nasal type) when it is diagnosed, which is most often at stage 1E or stage 2E, where ‘E’ stands for ‘extranodal’ (Li et al., 2018). Epidemically, NKTCL occurs more frequently in Latin America and East Asia than in European and American countries (Aozasa et al., 2008). Although the specific cause of the disease is still unknown, emerging evidence shows that morbidity of NKTCL is associated with Epstein-Barr virus (EBV) infection and chronic rhinitis (Bi et al., 2016). Almost all nasal NKTCL patients have suffered from chronic rhinitis or sinusitis (Naeimi et al., 2013); among these cases, EB virus infection accounts for more than 80 % (Macsween and Crawford, 2003). Apart from promoting and aggravating chronic rhinitis and sinusitis, EB virus infection also accelerates inflammatory lesions transforming to malignant lesions, finally developing into nasal ENKTCL (Asano et al., 2013).

Interleukin-6 (IL-6) is a cytokine reported at high concentrations and is deregulated in cancers (Fuster and Walsh, 2014). High IL-6 levels promote oncogenesis by regulating the tumor microenvironment, reflecting a strong association between inflammation and cancer (Kumari et al., 2016). Additionally, IL-6 may also act on other cell types within the tumor microenvironment and enhance tumor growth by facilitating angiogenesis (Gopinathan et al., 2015) and immune escape (Tanaka et al., 2014). In addition, the antitumor immunity-promoting effect of IL-6 has attracted intensive attention (Fisher et al., 2014). IL-6 is a main regulator of lymphocyte activation, proliferation and survival during active immune responses (Fisher et al., 2014). However, the relationship between IL-6 and ENKTCL growth and development is still unclear.

Chemotherapy, radiotherapy, and combined therapies are normally effective for localized natural killer/T-cell lymphoma, whereas the recurrence rate is high (Kohrt and Advani, 2009; Hu and Oki, 2018). The major problem in ENKTCL treatment is multidrug resistance (MDR) (Yamaguchi and Miyazaki, 2017).

In this study, to reveal the association between the tumor immune microenvironment and MDR in ENKTCL, we conducted in vitro and in vivo experiments on the roles of IL-6 in Adriamycin (ADM) resistance. We analyzed serum levels of IL-6 and tissue levels of ABCC4 in ENKTCL patients. Moreover, how IL-6 affected ADM resistance in ENKTCL was investigated.

Section snippets

Human patients

Fifty extranodal NK/T-cell lymphoma nasal type patients were enrolled in this project from 2013 to 2016 in the Department of Pathology, the First Affiliated Hospital of Zhengzhou University. None of the participants received chemoradiotherapy before biopsy collection. Thirty-four patients with chronic rhinitis were used as the control group. Detailed ENKTCL patient information is included in Table 1. This project strictly adhered to the Declaration of Helsinki and was approved by the Ethics

Serum levels of IL-6 were decreased and tissue levels of ABCC4 were increased in ENKTCL patients

First, to explore the function of IL-6 in MDR in ENKTCL, serum levels of IL-6 and tissue levels of Ki67 and ABCC4 were measured in chronic rhinitis patients and ENKTCL patients. The serum concentration of IL-6 was significantly decreased compared to that in chronic rhinitis patients (Fig. 1A). Fig. 1B revealed that the Ki67 expression score was highly positive for four points in tissues of nasal NK/T-cell lymphoma patients and negative for 1 point in chronic rhinitis patients, suggesting that

Discussion

Extranodal natural killer (NK)/T-cell lymphoma (ENKTCL), nasal type, is an invasive type of aggressive malignant lymphoma that occurs in the nasal cavity, paranasal sinuses and hard palate (Vasiwala et al., 2019). Radiotherapy, multidrug chemotherapy, and multidrug chemotherapy combined with external beam radiation therapy methods have been used to treat patients with ENKTCL and help prolong patient survival (Guo et al., 2008). Despite improvements in ENKTCL therapy, the number of patients who

Conclusion

In summary, our experiments revealed that serum levels of IL-6 were decreased and tissue levels of ABCC4 were increased in nasal NK/T-cell lymphoma patients. IL-6 promoted ADM-mediated growth suppression, induced cell arrest and enhanced apoptosis of SNK-6/ADM cells by inhibiting the upregulation of ABCC4 and negatively regulating the JAK2/STAT3/NF-κB/P65 pathway in nasal NK/T-cell lymphoma, thus sensitizing NK/T-cell lymphoma cells to ADM. Thus, our findings indicate that IL-6 is a potential

CRediT authorship contribution statement

Ming Gao: Conceptualization, Methodology, Software. Ming Gao and Liying Liu: Data curation, Writing - Original draft preparation. Xudong Zhang: Visualization, Investigation. Ming Gao: Supervision. Ming Gao and Sun Qi: Writing. Zhaoming Li and Mingzhi Zhang: Reviewing and Editing.

Declaration of Competing Interest

The authors report no declarations of interest.

Acknowledgement

This study was supported by funds from the National Natural Science Foundation of China (81570203).

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