JAK/STAT3 调控的脂肪酸 β-氧化对乳腺癌干细胞自我更新和化疗耐药至关重要。
JAK/STAT3-Regulated Fatty Acid β-Oxidation Is Critical for Breast Cancer Stem Cell Self-Renewal and Chemoresistance.
机构信息
Department of Immuno-Oncology, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA; Irell and Manella Graduate School of Biological Sciences, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA; LA Cell and Sorrento Therapeutics Inc., 4955 Director's Place, San Diego, CA 92121, USA.
Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
出版信息
Cell Metab. 2018 Jan 9;27(1):136-150.e5. doi: 10.1016/j.cmet.2017.11.001. Epub 2017 Dec 14.
Cancer stem cells (CSCs) are critical for cancer progression and chemoresistance. How lipid metabolism regulates CSCs and chemoresistance remains elusive. Here, we demonstrate that JAK/STAT3 regulates lipid metabolism, which promotes breast CSCs (BCSCs) and cancer chemoresistance. Inhibiting JAK/STAT3 blocks BCSC self-renewal and expression of diverse lipid metabolic genes, including carnitine palmitoyltransferase 1B (CPT1B), which encodes the critical enzyme for fatty acid β-oxidation (FAO). Moreover, mammary-adipocyte-derived leptin upregulates STAT3-induced CPT1B expression and FAO activity in BCSCs. Human breast-cancer-derived data suggest that the STAT3-CPT1B-FAO pathway promotes cancer cell stemness and chemoresistance. Blocking FAO and/or leptin re-sensitizes them to chemotherapy and inhibits BCSCs in mouse breast tumors in vivo. We identify a critical pathway for BCSC maintenance and breast cancer chemoresistance.
癌症干细胞（CSCs）对于癌症的进展和化疗耐药性至关重要。然而，脂质代谢如何调节 CSCs 和化疗耐药性仍然难以捉摸。在这里，我们证明 JAK/STAT3 调节脂质代谢，促进乳腺癌干细胞（BCSCs）和癌症化疗耐药性。抑制 JAK/STAT3 会阻止 BCSC 的自我更新和多种脂质代谢基因的表达，包括肉碱棕榈酰转移酶 1B（CPT1B），它编码脂肪酸β-氧化（FAO）的关键酶。此外，乳腺脂肪细胞衍生的瘦素上调 STAT3 诱导的 CPT1B 表达和 BCSC 中的 FAO 活性。来自人类乳腺癌的数据表明，STAT3-CPT1B-FAO 途径促进了癌细胞的干性和化疗耐药性。阻断 FAO 和/或瘦素可使它们对化疗重新敏感，并抑制体内小鼠乳腺癌肿瘤中的 BCSC。我们确定了维持 BCSC 和乳腺癌化疗耐药性的关键途径。
Zotero 插件