Pigment Epithelial-derived Factor (PEDF)-triggered Lung Cancer Cell Apoptosis Relies on p53 Protein-driven Fas Ligand (Fas-L) Up-regulation and Fas Protein Cell Surface Translocation

Lei Li,Ya-Chao Yao,Shu-Huan Fang,Cai-Qi Ma,Yi Cen,Zu-Min Xu,Zhi-Yu Dai,Cen Li,Shuai Li,Ting Zhang,Hong-Hai Hong,Wei-Wei Qi,Ti Zhou,Chao-Yang Li,Xia Yang,Guo-Quan Gao

doi:10.1074/jbc.m114.590000

Abstract

Pigment epithelium-derived factor (PEDF), a potent antiangiogenesis agent, has recently attracted attention for targeting tumor cells in several types of tumors. However, less is known about the apoptosis-inducing effect of PEDF on human lung cancer cells and the underlying molecular events. Here we report that PEDF has a growth-suppressive and proapoptotic effect on lung cancer xenografts. Accordingly, in vitro, PEDF apparently induced apoptosis in A549 and Calu-3 cells, predominantly via the Fas-L/Fas death signaling pathway. Interestingly, A549 and Calu-3 cells are insensitive to the Fas-L/Fas apoptosis pathway because of the low level of cell surface Fas. Our results revealed that, in addition to the enhancement of Fas-L expression, PEDF increased the sensitivity of A549 and Calu-3 cells to Fas-L-mediated apoptosis by triggering the translocation of Fas protein to the plasma membrane in a p53- and FAP-1-dependent manner. Similarly, the up-regulation of Fas-L by PEDF was also mediated by p53. Furthermore, peroxisome proliferator-activated receptor γ was determined to be the upstream regulator of p53. Together, these findings uncover a novel mechanism of tumor cell apoptosis induced by PEDF and provide a potential therapeutic strategy for tumors that are insensitive to Fas-L/Fas-dependent apoptosis because of a low level of cell surface Fas.

Highlights

Pigment epithelium-derived factor (PEDF) has attracted attention for its direct antitumor effect
It remains unclear whether PEDF can correct the deficiency of FITC-conjugated mouse anti-human CD95 (Fas) death signaling in lung cancer cells so that the tumor cells regain the ability to undergo apoptosis
Our results suggest that p53 activation was critical for the PEDF-induced Fas transport to the cell surface that resulted in the apoptosis of A549 and Calu-3 cells

Summary

Background

Results: The p53-mediated cell surface translocation of Fas and up-regulation of Fas-L contributes to PEDF-induced apoptosis. Conclusion: PEDF induces apoptosis by restoring the function of Fas death signaling in Fas-resistant lung cancer cells. Several studies have reported that frequent lack of cell surface Fas expression is present in various types of lung cancer cell lines, for example, in A549 [20], H720, and H69 cells [21] It remains unclear whether PEDF can correct the deficiency of Fas death signaling in lung cancer cells so that the tumor cells regain the ability to undergo apoptosis. The p53-mediated translocation of Fas to the plasma membrane, which restored the function of Fas death signaling, was involved in PEDF-induced apoptosis

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION