De novo sphingolipid biosynthesis necessitates detoxification in cancer cells
- Cell Rep. 2022 Sep 27;40(13):111415. doi: 10.1016/j.celrep.2022.111415.
- 1. Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01604, USA.
- 2. Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01604, USA.
- 3. School of Medicine, Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA.
- 4. Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01604, USA. Electronic address: [email protected].
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.