PTEN Dephosphorylates BECLIN-1 to Regulate Serum-Dependent Autophagy in Thyroid Cancer Cells

PTEN is a well-established tumor suppressor that plays a central role in the regulation of cell growth, metabolism, and survival. As a protein-lipid dual phosphatase, PTEN negatively regulates the PI3K/AKT signaling pathway, which in turn modulates autophagy, a conserved catabolic process that allows cells to degrade and recycle intracellular components, through the downstream effector mTORC1. While this represents the canonical mechanism by which PTEN influences autophagy, here we show that PTEN also regulates autophagy through an alternative, AKT-independent pathway. Specifically, through genetic manipulations of PTEN expression in thyroid cancer cells, we identify BECLIN-1 as a direct target of PTEN protein phosphatase activity. PTEN physically associates with BECLIN-1 under both basal and nutrient-deprived conditions, promoting its dephosphorylation at serine 295, thus relieving AKT inhibition resulting in autophagy activation. This regulatory event correlates with increased autophagic flux under starvation, as reflected by enhanced LC3 I to LC3 II conversion. Importantly, BECLIN-1 dephosphorylation is mediated by PTEN protein phosphatase activity and does not require its lipid phosphatase function. Furthermore, bioinformatic analyses reveal that high PTEN expression, together with enhanced autophagic activity (MAP1LC3B), is associated with improved clinical outcome in cancer patients. These findings uncover a direct, AKT-independent mechanism by which PTEN controls autophagy by modulating BECLIN-1 phosphorylation status. Together, our results provide novel insight into how PTEN coordinates cellular adaptation to metabolic stress and highlight an additional pathway through which PTEN regulates the autophagic machinery in cancer cells.