title: Proapoptotic PEDF functional peptides inhibit prostate tumor growth--a mechanistic study.
abstract: PEDF inhibits tumor growth via anti-angiogenic activity; however, the direct effect of PEDF on prostate carcinoma and its functional epitope as well as the underlying mechanism regulating the pathway from extracellular receptors to nuclear transcription factors has not been fully elucidated. This study investigates the ability and mechanism by which the functional PEDF peptides PEDF34 and PEDF44 suppress tumor growth. The results showed that death receptor pathway was activated by PEDF34 through up-regulation of FasL and activation of caspase-8 in both xenograft tumor tissues and PC-3 cells. FasL knockdown by siRNA or JNK-p inhibition attenuated apoptosis induced by PEDF34. NF-κB and PPARγ are crucial transcription factors for FasL expression. PEDF34 up-regulated PPARγ but did not affect NF-κB. PEDF34-induced up-regulation of FasL was abolished by siRNA-mediated PPARγ knockdown or using PPARγ inhibitor GW9662, whereas inhibition of NF-κB by the inhibitor PDTC or by siRNA had no effect. Furthermore, activation of JNK is necessary for PEDF34-induced up-regulation of FasL. PEDF34 has stronger hydropathicity and more interactions with laminin receptor than PEDF44. Blocking the laminin receptor abolished the up-regulation of FasL and PPARγ by PEDF34. Moreover, PEDF34 uses a similar mechanism to induce apoptosis in both endothelial and cancer cells. This study provides evidence that PEDF34, not PEDF44, serves as the proapoptotic epitope and exerts proapoptotic activity in both cancer and endothelial cells through activation of the extrinsic death receptor pathway. The dual anti-tumor and anti-angiogenic activities of PEDF34 suggest that it may be a promising agent for the treatment of prostate cancer.
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China; Department of Biochemistry, Guangzhou Medical University, Guangzhou, 510082, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Gong
authors.affiliation: Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
authors.forename: Shaopeng
authors.initials: S
authors.lastname: Qiu
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China; Department of Biochemistry, Guangzhou Medical University, Guangzhou, 510082, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China.
authors.forename: Yuedong
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, China.
authors.forename: Mingyuan
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
authors.forename: Yachao
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
authors.forename: Di
authors.initials: D
authors.lastname: Che
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Feng
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
authors.forename: Weibin
authors.initials: W
authors.lastname: Cai
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, U.S.A.
authors.forename: Jianxing
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
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, China. Electronic address: gaogq@mail.sysu.edu.cn.
authors.forename: Guoquan
authors.initials: G
authors.lastname: Gao
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China. Electronic address: yangzhh@mail.sysu.edu.cn.
authors.forename: Zhonghan
authors.initials: Z
authors.lastname: Yang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001483:Base Sequence; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D000939:Epitopes; D005136:Eye Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053222:Fas Ligand Protein / Q000378:metabolism; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic; D009414:Nerve Growth Factors / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D011487:Protein Conformation; D017474:Receptors, Laminin / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015843:Serpins / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D000970:Antineoplastic Agents; D053181:Caspase 8; D000939:Epitopes; D005136:Eye Proteins; D053222:Fas Ligand Protein; D016328:NF-kappa B; D009414:Nerve Growth Factors; D047495:PPAR gamma; D010446:Peptide Fragments; D017474:Receptors, Laminin; D011994:Recombinant Proteins; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor; C505661:FASLG protein, human
keywords: Apoptosis; Epitope; PEDF; PPARγ; Prostate carcinoma