Autophagy activation and SREBP‐1 induction contribute to fatty acid metabolic reprogramming by leptin in breast cancer cells

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.

Abbreviations

2‐DG

2‐deoxyglucose

3‐MA

3‐methyladenine

ACC‐1

acetyl‐CoA carboxylase 1

ACLY

ATP citrate lyase

ER

estrogen receptor

FADS1

fatty acid desaturase 1

FADS2

fatty acid desaturase 2

FAO

fatty acid oxidation

FAS

fatty acid synthesis

FASN

fatty acid synthase

FFA

free fatty acid

IHC

immunohistochemistry

SCD‐1

stearoyl‐CoA desaturase‐1

SREBP‐1

sterol regulatory element‐binding protein 1