BMB Reports 2019; 52(3): 220-225  https://doi.org/10.5483/BMBRep.2019.52.3.012
Links between accelerated replicative cellular senescence and down-regulation of SPHK1 transcription
Min Kyung Kim1, Wooseong Lee1, Gang-Ho Yoon2, Eun-Ju Chang1,2, Sun-Cheol Choi1,2,* & Seong Who Kim1,*
Departments of 1Biochemistry and Molecular Biology, 2Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
Correspondence to: Sun-Cheol Choi, Tel: +82-2-3010-2206; Fax: +82-2-3010-5307; E-mail: choisc@amc.seoul.kr; Seong Who Kim, Tel: +82-2-3010-4270; Fax: +82-2-477-4266; E-mail: swhokim@amc.seoul.kr
Received: January 7, 2019; Revised: January 16, 2019; Accepted: January 28, 2019; Published online: March 31, 2019.
© Korean Society for Biochemistry and Molecular Biology. All rights reserved.

cc This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
We have identified a mechanism to diminish the proliferative capacity of cells during cell expansion using human adiposederived stromal cells (hAD-SCs) as a model of replicative senescence. hAD-SCs of high-passage numbers exhibited a reduced proliferative capacity with accelerated cellular senescence. Levels of key bioactive sphingolipids were significantly increased in these senescent hAD-SCs. Notably, the transcription of sphingosine kinase 1 (SPHK1) was down-regulated in hAD-SCs at high-passage numbers. SPHK1 knockdown as well as inhibition of its enzymatic activity impeded the proliferation of hAD-SCs, with concomitant induction of cellular senescence and accumulation of sphingolipids, as seen in high-passage cells. SPHK1 knockdown-accelerated cellular senescence was attenuated by co-treatment with sphingosine-1-phosphate and an inhibitor of ceramide synthesis, fumonisin B1, but not by treatment with either one alone. Together, these results suggest that transcriptional down-regulation of SPHK1 is a critical inducer of altered sphingolipid profiles and enhances replicative senescence during multiple rounds of cell division.
Keywords: Human adipose-derived stromal cells, Replicative senescence, Sphingolipid, Sphingosine kinase 1, SPHK1 transcription


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