한빛사논문
- 조회243
Meghan E. Spears1, Namgyu Lee1, Sunyoung Hwang1, Sung Jin Park2, Anne E. Carlisle1, Rui Li1, Mihir B. Doshi1, Aaron M. Armando3, Jenny Gao1, Karl Simin1, Lihua Julie Zhu1, Paul L. Greer2, Oswald Quehenberger3, Eduardo M. Torres1, Dohoon Kim1,4
1Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01604, USA
2Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01604, USA
3School of Medicine, Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA
4Lead contact
Corresponding author: Dohoon Kim
Abstract
Sphingolipids play important signaling and structural roles in cells. Here, we find that during de novo sphingolipid biosynthesis, a toxic metabolite is formed with critical implications for cancer cell survival. The enzyme catalyzing the first step in this pathway, serine palmitoyltransferase complex (SPT), is upregulated in breast and other cancers. SPT is dispensable for cancer cell proliferation, as sphingolipids can be salvaged from the environment. However, SPT activity introduces a liability as its product, 3-ketodihydrosphingosine (3KDS), is toxic and requires clearance via the downstream enzyme 3-ketodihydrosphingosine reductase (KDSR). In cancer cells, but not normal cells, targeting KDSR induces toxic 3KDS accumulation leading to endoplasmic reticulum (ER) dysfunction and loss of proteostasis. Furthermore, the antitumor effect of KDSR disruption can be enhanced by increasing metabolic input (via high-fat diet) to allow greater 3KDS production. Thus, de novo sphingolipid biosynthesis entails a detoxification requirement in cancer cells that can be therapeutically exploited.
논문정보
- Research article
- 2022년 09월 (BRIC 등록일 2022-12-19)
- 국외 연구진
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