Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
Department of Pediatrics, State University of New York at Buffalo, Buffalo, NY, USA.
Cell Rep. 2024 Jul 23;43(7):114445. doi: 10.1016/j.celrep.2024.114445. Epub 2024 Jul 4.
Pro-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 Ca→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.
肿瘤发生中的生存代谢适应对压力的适应仍不太明确。我们发现，多发性骨髓瘤（MM）在基础和应激条件下出乎意料地依赖于长链脂肪酸（FA）的β氧化来生存。然而，在应激条件下，需要第二个生存信号来维持 FA 氧化（FAO）。我们之前发现 CD28 在 MM 细胞上表达，并传递显著的生存/化疗耐药信号。我们现在发现 CD28 信号转导调节自噬/脂噬，涉及 Ca→AMPK→ULK1 轴的激活，并通过 HuR 调节 ATG5 的翻译，导致持续的脂噬、增加的 FAO 和增强的 MM 生存。相反，阻断自噬/脂噬使 MM 在体内对化疗敏感。我们的发现将生存信号与 FA 的可利用性联系起来，FA 是在应激条件下维持癌症细胞生存所需的 FAO 所必需的，并将脂噬鉴定为克服 MM 治疗耐药性的治疗靶点。
