Prolyl isomerase Pin1 promotes autophagy and cancer cell viability through activating FoxO3 signalling

Cell Signal. 2024 Jan;113:110940. doi: 10.1016/j.cellsig.2023.110940. Epub 2023 Oct 30.ABSTRACTPin1-directed prolyl isomerization is a central common oncogenic mechanism to drive tumorigenic processes. However, the role of Pin1 in cellular autophagy is still poorly understood. Here we report that pharmacological inhibition of Pin1 decreased the formation of autophagosome/autolysosomes upon nutrient starvation. Inhibition of Pin1 reduced, whereas forced expression of Pin1 increased, the level of LC3 and viability of U2OS and PANC-1 cells. Pin1 could augment the accumulation of LC3 upon chloroquine treatment, while chloroquine also disturbed its function on cell viability. RNA-Seq and qPCR identified altered autophagic pathway upon Pin1 silencing. Mechanistically, FoxO3 was identified critical for Pin1-mediated autophagy. Knockdown of FoxO3 could rescue the changes of LC3 level and cellular viability caused by Pin1 overexpression. In xenograft mouse model, Pin1 reduced the sensitivity of PANC-1 to chloroquine while FoxO3 silencing could inhibit Pin1's function. Moreover, Pin1 could bind FoxO3 via its pS284-P motif, reduce its phosphorylation at T32, facilitate its nuclear retention, and therefore increased its transcriptional activity. S284A mutation of FoxO3 interfered with its T32 phosphorylation, reduced its nuclear localization and disrupted its function to support cell viability upon nutrient starvation. Furthermore, the protein level of Pin1 positively correlated with Fox...
Source: Cellular Signalling - Category: Cytology Authors: Source Type: research