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*

*Corresponding author for this work

Research output: Contribution to journalArticle

21 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)30785-30799
Number of pages15
JournalJournal of Biological Chemistry
Volume289
Issue number44
DOIs
StatePublished - Oct 31 2014

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Li, L., Yao, Y. C., Fang, S. H., Ma, C. Q., Cen, Y., Xu, Z. M., Dai, Z. Y., Li, C., Li, S., Zhang, T., Hong, H. H., Qi, W. W., Zhou, T., Li, C. Y., Yang, X., & Gao, G. Q. (2014). 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. Journal of Biological Chemistry, 289(44), 30785-30799. https://doi.org/10.1074/jbc.M114.590000