Journal
MOLECULAR ONCOLOGY
Volume 15, Issue 2, Pages 657-678Publisher
WILEY
DOI: 10.1002/1878-0261.12860
Keywords
autophagy; breast cancer; leptin; metabolic reprogramming; SREBP‐ 1
Categories
Funding
- Basic Science Research Program of the National Research Foundation of Korea (NRF) - Ministry of Education [NRF-2018R1D1A1B07049701]
- Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education [2020R1A6A1A03044512]
- National Research Foundation of Korea [4220200813731] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Leptin induces growth of breast cancer cells through reprogramming of lipid metabolism and activation of autophagy, with crucial roles played by SREBP-1 induction and fatty acid synthase induction. Autophagy mediates the metabolic effects of leptin on cancer cell-specific metabolism, highlighting its pivotal contribution to tumor growth.
Leptin, a hormone predominantly derived from adipose tissue, is well known to induce growth of breast cancer cells. However, its underlying mechanisms remain unclear. In this study, we examined the role of reprogramming of lipid metabolism and autophagy in leptin-induced growth of breast cancer cells. Herein, leptin induced significant increase in fatty acid oxidation-dependent ATP production in estrogen receptor-positive breast cancer cells. Furthermore, leptin induced both free fatty acid release and intracellular lipid accumulation, indicating a multifaceted effect of leptin in fatty acid metabolism. These findings were further validated in an MCF-7 tumor xenograft mouse model. Importantly, all the aforementioned metabolic effects of leptin were mediated via autophagy activation. In addition, SREBP-1 induction driven by autophagy and fatty acid synthase induction, which is mediated by SREBP-1, plays crucial roles in leptin-stimulated metabolic reprogramming and are required for growth of breast cancer cell, suggesting a pivotal contribution of fatty acid metabolic reprogramming to tumor growth by leptin. Taken together, these results highlighted a crucial role of autophagy in leptin-induced cancer cell-specific metabolism, which is mediated, at least in part, via SREBP-1 induction.
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