IL-6 promotes chemoresistance via upregulating CD36 mediated fatty acids uptake in acute myeloid leukemia

Yanjie Zhang; Hezhou Guo; Zhaoli Zhang; Wei Lu; Jiang Zhu; Jun Shi

doi:10.1016/j.yexcr.2022.113112

IL-6 promotes chemoresistance via upregulating CD36 mediated fatty acids uptake in acute myeloid leukemia

Exp Cell Res. 2022 Jun 1;415(1):113112. doi: 10.1016/j.yexcr.2022.113112. Epub 2022 Mar 25.

Authors

Yanjie Zhang¹, Hezhou Guo¹, Zhaoli Zhang¹, Wei Lu¹, Jiang Zhu², Jun Shi³

Affiliations

¹ Department of Hematology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, China.
² State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, China.
³ Department of Hematology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, China. Electronic address: junshi@sjtu.edu.cn.

PMID: 35346671
DOI: 10.1016/j.yexcr.2022.113112

Abstract

Chemoresistance contributes to poor survival and high relapse risk in acute myeloid leukemia (AML). As a pro-inflammatory cytokine, interleukin-6 (IL-6) plays a vital role in the chemoresistance of malignancies. However, the underlying mechanisms of chemoresistance in AML have not been widely studied. Lipid metabolism, which contributes to chemoresistance in AML, is enhanced by IL-6 in skeletal muscle cells. We hypothesized that IL-6 promotes the chemoresistance of AML by promoting lipid metabolism. Based on the positive correlation between IL-6 receptor expression and the cellular response to exogenous IL-6, we performed Gene Ontology analysis of a dataset consisting the information of 151 AML patients from The Cancer Genome Atlas. We found that lipid transport-associated genes were upregulated in the high IL-6 receptor expression group. Additionally, IL-6 promoted fatty acid (FA) uptake in both AML cell lines and primary AML cells. Inhibition of FA uptake by sulfo-N-succinimidyl oleate repressed IL-6-induced chemoresistance. Western blotting, quantitative polymerase chain reaction, and chromatin immunoprecipitation assays indicated that IL-6 promoted CD36 expression at both the mRNA and protein levels through stat3 signaling. Knockout of CD36 or stat3 repressed IL-6-induced FA uptake and chemoresistance. Furthermore, in five human AML samples, we validated that compared to CD36^-cells, CD36⁺ primary AML cells were less sensitive to cytosine arabinoside (Ara-c) and that blockade of CD36 re-sensitized CD36⁺ AML cells to Ara-c. Mice injected with CD36 knockout cells followed by treatment with Ara-c showed markedly decreased leukemia burden and prolonged survival in vivo. Finally, treatment with the CD36 antibody in combination with Ara-c exhibited synergistic effects in vivo. In conclusion, IL-6 promotes chemoresistance in AML through the stat3/CD36-mediated FA uptake. Blockade of CD36 improved the effect of Ara-c, representing a promising strategy for AML therapy.

Keywords: Acute myeloid leukemia; CD36; Chemoresistance; Fatty acid uptake; Interleukin-6.

MeSH terms

Animals
Cytarabine / pharmacology
Drug Resistance, Neoplasm*
Fatty Acids* / metabolism
Humans
Interleukin-6*
Leukemia, Myeloid, Acute* / drug therapy
Leukemia, Myeloid, Acute* / genetics
Leukemia, Myeloid, Acute* / pathology
Mice
Mice, Knockout
Receptors, Interleukin-6*

Substances

Fatty Acids
IL6 protein, human
IL6R protein, human
Interleukin-6
Receptors, Interleukin-6
Cytarabine