Abstract
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. Cancer stem cells play an important role in cancer development and chemoresistance. Wang et al. show that leptin-JAK/STAT3 regulates lipid metabolism through fatty acid β-oxidation (FAO), promoting breast cancer stemness and chemoresistance. Blocking FAO and/or depleting leptin re-sensitize cancer cells to chemotherapy while reducing cancer stemness in vivo.
Original language | English (US) |
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Pages (from-to) | 136-150.e5 |
Journal | Cell Metabolism |
Volume | 27 |
Issue number | 1 |
DOIs | |
State | Published - Jan 9 2018 |
Keywords
- JAK/STAT3
- breast cancer stem cell
- chemoresistance
- fatty acid β-oxidation
- leptin
ASJC Scopus subject areas
- Physiology
- Molecular Biology
- Cell Biology