Cowden syndrome-associated germline SDHD variants alter PTEN nuclear translocation through SRC-induced PTEN oxidation.
Bottom Line: However, very little is known about the underlying crosstalk between SDHD and PTEN in CS-associated thyroid cancer.We show that SRC inhibition could rescue SDHD dysfunction-induced cellular phenotype and tumorigenesis only when wild-type PTEN is expressed, in thyroid cancer lines.Patient lymphoblast cells carrying either SDHD-G12S or SDHD-H50R also show increased nuclear PTEN and more oxidized PTEN after hydrogen peroxide treatment.
Affiliation: Genomic Medicine Institute, Learner Research Institute.Show MeSH
Related in: MedlinePlus
Mentions: We previously found that cellular ROS is significantly increased in CS/CSL patient samples harboring germline SDHx variants compared with normal controls (16). To determine if the SDHD variants in thyroid cancer cells can result in damage to lipids by, e.g. lipid peroxidation, we measured the byproducts of polyunsaturated fatty acid peroxides upon decomposition, namely, malondialdehyde (MDA) and 4-hydroxyalkenals (24) in two thyroid cancer cell lines follicular thyroid carcinoma (FTC) 133-PTEN wild-type and FTC236-PTEN cells transfected with SDHD-G12S or -H50R. Compared with control SDHD-wild-type (25) transfected cells, no significant increase of lipid peroxidation was observed in FTC133-PTEN wild-type cells with SDHD-G12S or SDHD-H50R. In contrast, a slight increase in lipid peroxidation was observed in SDHD-G12S or SDHD-H50R transfected FTC236-PTEN cells (Fig. 1A). We therefore surmised that wild-type PTEN in FTC133-PTEN wild type could play a protective role against SDHD variant-induced oxidative stress.Figure 1.
Affiliation: Genomic Medicine Institute, Learner Research Institute.