Peng, PengChavel, ColinLiu, WenshengCarlson, Louise M.Cao, ShaUtley, AdamOlejniczak, Scott H.Lee, Kelvin P.2024-10-162024-10-162024Peng P, Chavel C, Liu W, et al. Pro-survival signaling regulates lipophagy essential for multiple myeloma resistance to stress-induced death. Cell Rep. 2024;43(7):114445. doi:10.1016/j.celrep.2024.114445https://hdl.handle.net/1805/44019Pro-survival metabolic adaptations to stress in tumorigenesis remain less well defined. We find that multiple myeloma (MM) is unexpectedly dependent on beta-oxidation of long-chain fatty acids (FAs) for survival under both basal and stress conditions. However, under stress conditions, a second pro-survival signal is required to sustain FA oxidation (FAO). We previously found that CD28 is expressed on MM cells and transduces a significant pro-survival/chemotherapy resistance signal. We now find that CD28 signaling regulates autophagy/lipophagy that involves activation of the Ca2+→AMPK→ULK1 axis and regulates the translation of ATG5 through HuR, resulting in sustained lipophagy, increased FAO, and enhanced MM survival. Conversely, blocking autophagy/lipophagy sensitizes MM to chemotherapy in vivo. Our findings link a pro-survival signal to FA availability needed to sustain the FAO required for cancer cell survival under stress conditions and identify lipophagy as a therapeutic target to overcome treatment resistance in MM.en-USAttribution-NonCommercial-NoDerivatives 4.0 InternationalCD28CancerMetabolismAutophagyFatty acid metabolismFatty acid oxidationLipid dropletsLipophagyMultiple myelomaPro-survival regulationArticle