Suppression of fatty acid oxidation supports pancreatic cancer growth and survival under hypoxic conditions through autophagy induction.
Byungjoo KimJihye GwakMinjoong KimSeungyeon YangSunsook HwangSeungmin ShinJi Hye KimJaekyoung SonSeung Min JeongPublished in: Cancer gene therapy (2023)
Hypoxia, one of the key features of solid tumors, induces autophagy, which acts as an important adaptive mechanism for tumor progression under hypoxic environment. Cellular metabolic reprogramming has been correlated with hypoxia, but the molecular connection to the induction of autophagy remains obscure. Here, we show that suppression of fatty acid oxidation (FAO) by hypoxia induces autophagy in human pancreatic ductal adenocarcinoma (PDAC) cells that is required for their growth and survival. Reduced cellular acetyl-CoA levels caused by FAO inhibition decreases LC3 acetylation, resulting in autophagosome formation. Importantly, PDAC cells are significantly dependent on this metabolic reprogramming, as improving FAO leads to a reduction in hypoxia-induced autophagy and an increase in cell death after chemotherapy. Thus, our study supports that suppression of FAO is an important metabolic response to hypoxia and indicates that targeting this pathway in PDAC may be an effective therapeutic approach.
Keyphrases
- cell death
- cell cycle arrest
- endoplasmic reticulum stress
- induced apoptosis
- fatty acid
- endothelial cells
- signaling pathway
- oxidative stress
- squamous cell carcinoma
- pi k akt
- hydrogen peroxide
- radiation therapy
- cancer therapy
- drug delivery
- locally advanced
- cell proliferation
- simultaneous determination
- long non coding rna
- single molecule
- visible light