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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Palmitic acid negatively regulates tumor suppressor PTEN through T366 phosphorylation and protein degradation.

Authors: Bai, Dongmei; Wu, Yong; Deol, Poonamjot; Nobumori, Yumiko; Zhou, Qi; Sladek, Frances M; Liu, Xuan

Published In Cancer Lett, (2021 Jan 01)

Abstract: Chronic elevated free fatty (FFA) levels are linked to metabolic disorders and tumorigenesis. However, the molecular mechanism by which FFAs induce cancer remains poorly understood. Here, we show that the tumor suppressor PTEN protein levels were decreased in high fat diet (HFD) fed mice. As palmitic acid (PA, C16:0) showed a significant increase in the HFD fed mice, we further investigated its role in PTEN down regulation. Our studies revealed that exposure of cells to high doses of PA induced mTOR/S6K-mediated phosphorylation of PTEN at T366. The phosphorylation subsequently enhanced the interaction of PTEN with the E3 ubiquitin ligase WW domain-containing protein 2 (WWP2), which promoted polyubiquitination of PTEN and protein degradation. Consistent with PTEN degradation, exposure of cells to increased concentrations of PA also promoted PTEN-mediated AKT activation and cell proliferation. Significantly, a higher level of S6K activation, PTEN T366 phosphorylation, and AKT activation were also observed in the livers of the HFD fed mice. These results provide a molecular mechanism by which a HFD and elevated PA regulate cell proliferation through inactivation of tumor suppressor PTEN.

PubMed ID: 33039560 Exiting the NIEHS site

MeSH Terms: Animals; Cell Proliferation*; Colonic Neoplasms/drug therapy; Colonic Neoplasms/metabolism; Colonic Neoplasms/pathology*; Enzyme Inhibitors/pharmacology; HCT116 Cells; Humans; Male; Mice; Mice, Inbred C57BL; Obesity/etiology; Obesity/metabolism; Obesity/pathology*; PTEN Phosphohydrolase/genetics; PTEN Phosphohydrolase/metabolism*; Palmitic Acid/pharmacology*; Phosphorylation; Proteolysis; Proto-Oncogene Proteins c-akt/genetics; Proto-Oncogene Proteins c-akt/metabolism; Signal Transduction; TOR Serine-Threonine Kinases/genetics; TOR Serine-Threonine Kinases/metabolism; Threonine/chemistry; Threonine/genetics; Threonine/metabolism*; Ubiquitination

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