JAK/STAT3-Regulated Fatty Acid β-Oxidation Is Critical for Breast Cancer Stem Cell Self-Renewal and Chemoresistance.,Cell Metabolism

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JAK/STAT3-Regulated Fatty Acid β-Oxidation Is Critical for Breast Cancer Stem Cell Self-Renewal and Chemoresistance.
Cell Metabolism ( IF 27.7 ) Pub Date : 2018-Jan-09 , DOI: 10.1016/j.cmet.2017.11.001
Tianyi Wang ₁ , Johannes Francois Fahrmann ₂ , Heehyoung Lee ₃ , Yi-Jia Li ₄ , Satyendra C Tripathi ₂ , Chanyu Yue ₃ , Chunyan Zhang ₄ , Veronica Lifshitz ₄ , Jieun Song ₄ , Yuan Yuan ₅ , George Somlo ₅ , Rahul Jandial ₆ , David Ann ₇ , Samir Hanash ₂ , Richard Jove ₈ , Hua Yu ₄

Affiliation

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.
Department of Immuno-Oncology, Beckman Research Institute and 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 Immuno-Oncology, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
Department of Medical Oncology & Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
Department of Surgery, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
Department of Diabetes Complications and Metabolism, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
Therapy Institute, Department of Biomedical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33314, USA.

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.

中文翻译：

JAK / STAT3调节的脂肪酸β-氧化对于乳腺癌干细胞的自我更新和抗化学性至关重要。

癌症干细胞（CSC）对于癌症进展和化学耐药性至关重要。脂质代谢如何调节CSC和化学抗药性仍不清楚。在这里，我们证明JAK / STAT3调节脂质代谢，从而促进乳腺CSCs（BCSCs）和癌症化学耐药性。抑制JAK / STAT3会阻断BCSC的自我更新和多种脂质代谢基因的表达，其中包括肉碱棕榈酰转移酶1B（CPT1B），该酶编码脂肪酸β-氧化的关键酶（FAO）。此外，乳腺脂肪细胞来源的瘦素上调了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途径可促进癌细胞的干性和化学抗性。阻断FAO和/或瘦蛋白会使它们对化疗重新敏感，并在体内抑制小鼠乳腺肿瘤中的BCSC。

更新日期：2017-12-15

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