PEDF inhibits non‑small cell lung cancer proliferation by suppressing autophagy through downregulation of AMPK‑ULK1 signaling

Abstract

Current investigations suggest that pigment epithelial-derived factor (PEDF) can mediate the progression of non-small cell lung cancer (NSCLC) by regulating autophagy. However, the underlying mechanisms associated with autophagy remain poorly elucidated. The aim of the present study was to investigate the association between the PEDF/adenosine 5'-monophosphate-activated protein kinase (AMPK)/Unc-51 like autophagy-activated kinase 1 (ULK1) pathway and autophagy in NSCLC. Intracellular autophagy was evaluated using indicators such as the expression and activation of microtubule-associated protein light chain 3-I (LC3-I), LC3-II and p62, as well as the distribution and number of autophagosomes observed by confocal microscopy. In addition, the activity and proliferative capacity of NSCLC cells under PEDF overexpression was also examined using Cell Counting Kit-8 and lactate dehydrogenase (LDH) assays, and western blotting (WB) of related proteins. The results revealed that PEDF significantly inhibited NSCLC cell proliferation and viability, and increased LDH release and intercellular adhesion. Furthermore, PEDF suppressed the expression and activation of LC-3 and reduced the number and distribution of autophagosomes. The PEDF-induced inhibition of autophagy exhibited a direct association with the suppressed proliferation capacity and cell viability of NSCLC cells. The results of WB showed that NSCLC cells regulated autophagy through the AMPK/ULK1 signaling pathway. PEDF downregulated the AMPK/ULK1 signaling pathway, and AMPK or ULK1 overexpression markedly reduced the inhibitory effect of PEDF on autophagy. In conclusion, PEDF overexpression significantly inhibited the proliferative capacity and cell viability of NSCLC cells, as PEDF exerted an inhibitory function by regulating autophagy in NSCLC cells. Finally, it was demonstrated that autophagy may be suppressed by inhibiting the AMPK/ULK1 signaling pathway, thereby revealing a mechanism of lung cancer progression.

Global research and emerging trends in autophagy in lung cancer: a bibliometric and visualized study from 2013 to 2022

“…However, in the later stages of tumor development, the absence of autophagy may result in the accumulation of mitochondrial defects, ultimately suppressing tumor growth ( Strohecker et al, 2013 ). Various genes and signaling pathways, such as PARP1-mediated AMPK-mTOR, RPL11, COTE-1, PINK1, PEDF, and MALAT1, have been identified to play critical roles in regulating autophagy and influencing lung cancer cell proliferation, migration, and invasion ( Ma et al, 2018 ; Lu et al, 2020 ; Miao et al, 2022 ; Chen et al, 2023 ; Ma et al, 2023 ; Zhang et al, 2023 ). Additionally, certain compounds, such as the metal, Cd, schizandrin A, pinocembrin, adenine aldehyde, and inhibitors of basal autophagy, have been found to induce autophagy in lung cancer cells, affecting proliferation and migration ( Kaminskyy et al, 2012 ; Wang et al, 2020 ; Gong, 2021 ; Zhu et al, 2021 ; Ghemrawi et al, 2023 ).…”