title: 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.
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.
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China,; Department of Reproductive Medicine Center, Key Laboratory for Reproductive Medicine of Guangdong Province, Third Affiliated Hospital of Guangzhou Medical University, 63 Duobao Road, Guangzhou 510150, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Laboratory Center of Guangdong No. 2 Provincial People's Hospital, Guangzhou 510317, Guangdong Province, China.
authors.forename: Ya-Chao
authors.initials: YC
authors.lastname: Yao
authors.affiliation: DME Center, Clinical Pharmacology Institute, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
authors.forename: Shu-Huan
authors.initials: SH
authors.lastname: Fang
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Cai-Qi
authors.initials: CQ
authors.lastname: Ma
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Cen
authors.affiliation: Cancer Center, Affiliated Hospital of Guangdong Medical College, Zhanjiang 524000, China.
authors.forename: Zu-Min
authors.initials: ZM
authors.lastname: Xu
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Zhi-Yu
authors.initials: ZY
authors.lastname: Dai
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Cen
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Hong-Hai
authors.initials: HH
authors.lastname: Hong
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Qi
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Ti
authors.initials: T
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China,. Electronic address: clioffice@yahoo.cn.
authors.forename: Chao-Yang
authors.initials: CY
authors.lastname: Li
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China,; China Key Laboratory of Tropical Disease Control, Sun Yat-sen University, Ministry of Education, Guangzhou 510080, China, and. Electronic address: yangxia@mail.sysu.edu.cn.
authors.forename: Xia
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China,; Key Laboratory of Functional Molecules from Marine Microorganisms, Sun Yat-sen University, Department of Education of Guangdong Province, Guangdong 510080, China. Electronic address: gaogq@mail.sysu.edu.cn.
authors.forename: Guo-Quan
authors.initials: GQ
authors.lastname: Gao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005136:Eye Proteins / Q000494:pharmacology* / Q000502:physiology / Q000627:therapeutic use; D053222:Fas Ligand Protein / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D009414:Nerve Growth Factors / Q000494:pharmacology* / Q000502:physiology / Q000627:therapeutic use; D047495:PPAR gamma / Q000378:metabolism; D021381:Protein Transport; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13 / Q000378:metabolism; D015843:Serpins / Q000494:pharmacology* / Q000502:physiology / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays; D019014:fas Receptor / Q000378:metabolism*; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D000970:Antineoplastic Agents; D053181:Caspase 8; D005136:Eye Proteins; D053222:Fas Ligand Protein; D009414:Nerve Growth Factors; D047495:PPAR gamma; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13; D015843:Serpins; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; D000099174:Pigment Epithelium-Derived Factor; C491901:FAS protein, human; C495901:TP53 protein, human; C516742:PTPN13 protein, human; C505530:CASP8 protein, human
keywords: Apoptosis; Cancer Therapy; Cell Death; Lung Cancer; Molecular Cell Biology; p53