Therapy-induced senescence is a state of cell cycle arrest that occurs as a response to various chemotherapeutics. Senescent cells display resistance to cell death, which impairs efficacy of chemotherapeutic strategies. Since lipids exhibit pro-survival bioactivity, we envisioned that probing the lipidome can provide novel insights into pathways that can be explored to induce cell death in senescent cells and provide novel therapeutic strategies. Therefore, we studied the changes in the cellular lipidome during therapy-induced senescence using untargeted lipidomics in order to identify significant changes in lipid composition as cells become senescent in a colorectal cancer cell line. Among the thousands of lipid species detected, we identified eighteen species that showed significant and profound changes in senescent cells. Sixteen of these species were atypical sphingolipids, 1-deoxyceramides, which were depleted in senescent cells. Unlike their canonical counterpart, ceramides, 1-deoxyceramides cannot be converted to more complex sphingolipids or degrade into sphingosine, which makes deoxyceramides critical players of sphingolipid processing in cells. Elevating the levels of deoxyceramides by supplementing the growth medium with metabolic precursors or by directly adding deoxyceramide results in decreased senescence, showing that these species play a key role in this process. To elucidate the effects of changes in deoxyceramide levels in senescence, we designed a focused small molecule screen and investigated senescence phenotype when specific sphingolipid-processing enzymes were inactivated. This approach led to the identification of a ceramide-processing enzyme, the inhibition of which reduced therapy-induced senescence levels in colon cancer cells. Our current efforts are towards understanding the mechanism through which deoxyceramides and the ceramide-processing enzyme we identified affect cell fate during senescence, with the goal of prioritizing lipid-processing enzymes which can be targeted to perturb senescence in cancer cells and improve therapeutic outcome.

Deoxyceramides modulate therapy-induced senescence

ACS Fall 2021

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