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: To further identify the effect of our SRC kinase inhibitor on thyroid cancer cell lines, we examined the activation of HIF-1α by ROS with or without SRC inhibition. In FTC133-PTEN wild-type cells expressing SDHD-G12S or SDHD-H50R, H2O2 treatment dramatically induced HIF-1α expression, with the levels of increased expression in SDHD-G12S or SDHD-H50R-containing cells much more dramatic compared with those from control (SDHD-WT) cells. Pretreatment with bosutinib was associated with blockade of the increased HIF-1α expression from H2O2 exposure in both SDHD-G12S/H50R expressing cells and control (SDHD-wild-type) cells (Fig. 4A). Consistently, we observed further increases of HIF-1α expression in SDHD-silenced cells compared with control cells (transfected with empty plasmid), and this increased HIF-1α expression was also blocked by bosutinib pretreatment (Fig. 4B).Figure 4.
Affiliation: Genomic Medicine Institute, Learner Research Institute.