title: Platelet factor 4 induces cell apoptosis by inhibition of STAT3 via up-regulation of SOCS3 expression in multiple myeloma.
abstract: Platelet factor 4 (PF4) is an angiostatic chemokine that suppresses tumor growth and metastasis. We previously revealed frequent transcriptional silencing of PF4 in multiple myeloma, but the functional roles of this chemokine are still unknown. We studied the apoptotic effects of PF4 on myeloma cell lines and primary myeloma in vitro, and investigated the involved signaling pathway. The in vivo effects were also studied using a mouse model. PF4 not only suppressed myeloma-associated angiogenesis, but also inhibited growth and induced apoptosis in myeloma cells. We found that PF4 negatively regulated STAT3 and concordantly inhibited constitutive and interleukin-6-induced phosphorylation of STAT3, and down-regulated the expression of STAT3 target genes (Mcl-1, survivin and VEGF). Overexpression of constitutively activated STAT3 could rescue PF4-induced apoptotic effects. Furthermore, we found that PF4 induced the expression of SOCS3, a STAT3 inhibitor, and gene silencing of SOCS3 abolished its ability to inhibit STAT3 activation, suggesting a critical role of SOCS3 in PF4-induced STAT3 inhibition. Knockdown of LRP1, a putative PF4 receptor, could also abolish PF4-induced apoptosis and STAT3 inhibition. Finally, the tumor growth inhibitory effect of PF4 was confirmed by in vivo mouse models. Immunostaining of rabbit bone xenografts from PF4-treated mice showed induction of apoptosis of myeloma cells and inhibition of angiogenesis, which was associated with suppression of STAT3 activity. Together, our preclinical data indicate that PF4 may be a potential new targeting agent for the treatment of myeloma.
authors.affiliation: Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, the Chinese University of Hong Kong, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Liang
authors.forename: Suk Hang
authors.initials: SH
authors.lastname: Cheng
authors.forename: Chi Keung
authors.initials: CK
authors.lastname: Cheng
authors.forename: Kin Mang
authors.initials: KM
authors.lastname: Lau
authors.forename: Shek Ying
authors.initials: SY
authors.lastname: Lin
authors.forename: Eudora Y D
authors.initials: EY
authors.lastname: Chow
authors.forename: Natalie P H
authors.initials: NP
authors.lastname: Chan
authors.forename: Rosalina K L
authors.initials: RK
authors.lastname: Ip
authors.forename: Raymond S M
authors.initials: RS
authors.lastname: Wong
authors.forename: Margaret H L
authors.initials: MH
authors.lastname: Ng
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D009389:Neovascularization, Pathologic; D010766:Phosphorylation / Q000187:drug effects; D010978:Platelet Factor 4 / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics*
chemical_list: D015850:Interleukin-6; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D010978:Platelet Factor 4