肿瘤发生过程中对应激的促生存代谢适应尚不明确。我们发现，多发性骨髓瘤（MM）出人意料地依赖于长链脂肪酸（FA）的β氧化，以便在基础和应激条件下生存。然而，在应激条件下，需要第二个促生存信号来维持 FA 氧化 (FAO)。我们之前发现 CD28 在 MM 细胞上表达并转导显着的促生存/化疗耐药信号。我们现在发现 CD28 信号传导调节自噬/脂肪吞噬，涉及 Ca2→AMPK→ULK1 轴的激活，并通过 HuR 调节 ATG5 的翻译，从而导致持续的脂肪吞噬、增加FAO并增强 MM 存活率。相反，阻断自噬/脂肪吞噬会使 MM 对体内化疗敏感。我们的研究结果将促生存信号与维持癌细胞在应激条件下生存所需的 FA 所需的 FA 可用性联系起来，并将脂肪吞噬确定为克服 MM 治疗耐药性的治疗目标。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

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 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.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.