Oxidized Phospholipids in Tumor Microenvironment Stimulate Tumor Metastasis via Regulation of Autophagy.
Jin Kyung SeokEun-Hee HongGabsik YangHye Eun LeeSin-Eun KimKwang-Hyeon LiuHan Chang KangYong-Yeon ChoHye Suk LeeJoo Young LeePublished in: Cells (2021)
Oxidized phospholipids are well known to play physiological and pathological roles in regulating cellular homeostasis and disease progression. However, their role in cancer metastasis has not been entirely understood. In this study, effects of oxidized phosphatidylcholines such as 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC) on epithelial-mesenchymal transition (EMT) and autophagy were determined in cancer cells by immunoblotting and confocal analysis. Metastasis was analyzed by a scratch wound assay and a transwell migration/invasion assay. The concentrations of POVPC and 1-palmitoyl-2-glutaroyl-sn-glycero-phosphocholine (PGPC) in tumor tissues obtained from patients were measured by LC-MS/MS analysis. POVPC induced EMT, resulting in increase of migration and invasion of human hepatocellular carcinoma cells (HepG2) and human breast cancer cells (MCF7). POVPC induced autophagic flux through AMPK-mTOR pathway. Pharmacological inhibition or siRNA knockdown of autophagy decreased migration and invasion of POVPC-treated HepG2 and MCF7 cells. POVPC and PGPC levels were greatly increased at stage II of patient-derived intrahepatic cholangiocarcinoma tissues. PGPC levels were higher in malignant breast tumor tissues than in adjacent nontumor tissues. The results show that oxidized phosphatidylcholines increase metastatic potential of cancer cells by promoting EMT, mediated through autophagy. These suggest the positive regulatory role of oxidized phospholipids accumulated in tumor microenvironment in the regulation of tumorigenesis and metastasis.
Keyphrases
- epithelial mesenchymal transition
- cell death
- signaling pathway
- breast cancer cells
- low density lipoprotein
- endoplasmic reticulum stress
- endothelial cells
- induced apoptosis
- gene expression
- oxidative stress
- high glucose
- cell cycle arrest
- diabetic rats
- transforming growth factor
- newly diagnosed
- high throughput
- end stage renal disease
- squamous cell carcinoma
- small cell lung cancer
- fatty acid
- induced pluripotent stem cells
- ejection fraction
- cell proliferation
- skeletal muscle
- drug induced
- pluripotent stem cells
- peritoneal dialysis
- transcription factor
- prognostic factors
- cell migration
- young adults
- raman spectroscopy
- drug delivery
- cancer therapy
- surgical site infection
- stress induced
- patient reported outcomes