Hypoxia‑induced SREBP1‑mediated lipogenesis and autophagy promote cell survival via fatty acid oxidation in breast cancer cells

Jung,Jae-Ha; Yang,Yeseul; Kim,Yongbaek

doi:10.3892/ol.2025.14921

Hypoxia‑induced SREBP1‑mediated lipogenesis and autophagy promote cell survival via fatty acid oxidation in breast cancer cells

Authors:
- Jae-Ha Jung
- Yeseul Yang
- Yongbaek Kim
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Affiliations: Laboratory of Clinical Pathology, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea
Published online on: February 7, 2025 https://doi.org/10.3892/ol.2025.14921
Article Number: 175
Copyright: © Jung et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

In the hypoxic tumor microenvironment, cancer cells undergo metabolic reprogramming to survive. The present study aimed to assess the effects of hypoxic conditions on the lipid metabolism of breast cancer cells to elucidate the mechanisms by which cancer cells survive in an unfavorable environment. Cell viability was assessed by trypan blue staining, MTT and Annexin V‑PI assays. Intracellular lipid levels were quantified using Nile red stain with immunofluorescence (IF). Autophagy was detected using LC3 antibody, Cyto‑ID stain, IF, Western blotting, and flow cytometry. Fatty acid oxidation (FAO) and ATP production were analyzed using specific assays, while gene expression was assessed by reverse transcription‑polymerase chain reaction. siRNA transfection was used for gene knockdown, and Kaplan‑Meier analysis was performed for survival analysis. Fatostatin and rapamycin served as an inhibitor of sterol regulatory element‑binding protein 1 (SREBP1) and an autophagy inducer, respectively. Under hypoxic conditions, triple‑negative breast cancer (TNBC) MDA‑MB‑231 cells showed markedly increased survival and proliferation rates compared with normal cells (MCF‑10A) and estrogen receptor‑positive cells (MCF‑7), with no change in apoptosis. Under hypoxic conditions, MDA‑MB‑231 cells showed increased expression of lipogenesis, autophagy and FAO‑related enzymes and activation of SREBP1, a key transcription factor for lipogenic genes, whereas these changes were not observed in MCF‑7 cells. When SREBP1 was inhibited with chemical inhibitors and siRNA, the expression of lipogenic, autophagic and FAO‑related enzymes decreased, resulting in reduced ATP production and viability in hypoxic MDA‑MB‑231 cells; however, this effect was restored when an autophagy inducer was added. Kaplan‑Meier analysis demonstrated that higher SREBP1 expression in patients with TNBC was associated with a worse prognosis, suggesting that SREBP1‑mediated reprogramming of lipid metabolism and autophagy under hypoxia is essential for TNBC cell survival. The results of the present study indicate that strategies targeting SREBP1 could be exploited to treat TNBC and improve prognosis.

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