Ceramide Metabolism Regulated by Sphingomyelin Synthase 2 Is Associated with Acquisition of Chemoresistance via Exosomes in Human Leukemia Cells

Makoto Taniguchi; Shingo Nagaya; Kohei Yuyama; Ai Kotani; Yasuyuki Igarashi; Toshiro Okazaki

doi:10.3390/ijms231810648

Ceramide Metabolism Regulated by Sphingomyelin Synthase 2 Is Associated with Acquisition of Chemoresistance via Exosomes in Human Leukemia Cells

Int J Mol Sci. 2022 Sep 13;23(18):10648. doi: 10.3390/ijms231810648.

Authors

Makoto Taniguchi¹, Shingo Nagaya^{2

3}, Kohei Yuyama⁴, Ai Kotani⁵, Yasuyuki Igarashi⁴, Toshiro Okazaki²

Affiliations

¹ Medical Research Institute, Kanazawa Medical University, Uchinada 920-0293, Japan.
² Research Institute for Bioresources and Biotechnology, Ishikawa Prefectural University, Nonoichi 921-8836, Japan.
³ Material Research Department, Shalom Co., Ltd., Oshino 401-0511, Japan.
⁴ Lipid Biofunction Section, Frontier Research Center for Advanced Material and Life Science, Faculty of Advanced Life Science, Hokkaido University, Sapporo 001-0021, Japan.
⁵ Department of Hematological Malignancy, Institute of Medical Sciences, Tokai University, Isehara 259-1193, Japan.

Abstract

Ceramide levels controlled by the sphingomyelin (SM) cycle have essential roles in cancer cell fate through the regulation of cell proliferation, death, metastasis, and drug resistance. Recent studies suggest that exosomes confer cancer malignancy. However, the relationship between ceramide metabolism and exosome-mediated cancer malignancy is unclear. In this study, we elucidated the role of ceramide metabolism via the SM cycle in exosomes and drug resistance in human leukemia HL-60 and adriamycin-resistant HL-60/ADR cells. HL-60/ADR cells showed significantly increased exosome production and release compared with parental chemosensitive HL-60 cells. In HL-60/ADR cells, increased SM synthase (SMS) activity reduced ceramide levels, although released exosomes exhibited a high ceramide ratio in both HL-60- and HL-60/ADR-derived exosomes. Overexpression of SMS2 but not SMS1 suppressed intracellular ceramide levels and accelerated exosome production and release in HL-60 cells. Notably, HL-60/ADR exosomes conferred cell proliferation and doxorubicin resistance properties to HL-60 cells. Finally, microRNA analysis in HL-60 and HL-60/ADR cells and exosomes showed that miR-484 elevation in HL-60/ADR cells and exosomes was associated with exosome-mediated cell proliferation. This suggests that intracellular ceramide metabolism by SMS2 regulates exosome production and release, leading to acquisition of drug resistance and enhanced cell proliferation in leukemia cells.

Keywords: ceramide; doxorubicin; drug resistance; exosome; leukemia; miR-484; microRNA; sphingomyelin; sphingomyelin synthase.

MeSH terms

Ceramides / metabolism
Doxorubicin / pharmacology
Drug Resistance, Neoplasm
Exosomes* / metabolism
Humans
Leukemia*
MicroRNAs* / genetics
Sphingomyelins / metabolism
Transferases (Other Substituted Phosphate Groups)

Substances

Ceramides
MicroRNAs
Sphingomyelins
Doxorubicin
Transferases (Other Substituted Phosphate Groups)
phosphatidylcholine-ceramide phosphocholine transferase

Grants and funding

This work was partly supported by: the JSPS KAKENHI (grant/award number: 21K06827 to M.T., 18K06456 to K.Y., 20K21550 to A.K., and 22H02926 to T.O.); the Takeda Science Foundation; the Strategic Research Foundation Grant-Aided Project for Private Universities, the Ministry of Education, Culture, Sports, Science and Technology (MEXT) (grant number S1201004 to T.O.) in Japan; Ono Pharmaceutical Co., LTD. (to T.O.); and CREST from Japan Science and Technology Agency (JST) (grant number JPMJCR19H5 to A.K.).