Prostate-specific antitumor activity by probasin promoter-directed p202 expression.
p202, an interferon (IFN) inducible protein, arrests cell cycle at G1 phase leading to cell growth retardation. We previously showed that ectopic expression of p202 in human prostate cancer cells renders growth inhibition and suppression of transformation phenotype in vitro. In this report, we showed that prostate cancer cells with stable expression of p202 were less tumorigenic than the parental cells. The antitumor activity of p202 was further demonstrated by an ex vivo treatment of prostate cancer cells with p202 expression vector that showed significant tumor suppression in mouse xenograft model. Importantly, to achieve a prostate-specific antitumor effect by p202, we employed a prostate-specific probasin (ARR2PB) gene promoter to direct p202 expression (ARR2PB-p202) in an androgen receptor (AR)-positive manner. The ARR2PB-p202/liposome complex was systemically administered into mice bearing orthotopic AR-positive prostate tumors. We showed that parenteral administration of an ARR2PB-p202/liposome preparation led to prostate-specific p202 expression and tumor suppression in orthotopic prostate cancer xenograft model. Furthermore, with DNA array technique, we showed that the expression of p202 was accompanied by downregulation of G2/M phase cell-cycle regulators, cyclin B, and p55cdc. Together, our results suggest that p202 suppresses prostate tumor growth, and that a prostate-specific antitumor effect can be achieved by systemic administration of liposome-mediated delivery of ARR2PB-p202.
Wen
Yong
Y
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Giri
Dipak
D
Yan
Duen-Hwa
DH
Spohn
Bill
B
Zinner
Ralph G
RG
Xia
Weiya
W
Thompson
Timothy C
TC
Matusik
Robert J
RJ
Hung
Mien-Chie
MC
D000727:Androgen-Binding Protein / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D015536:Down-Regulation; D015870:Gene Expression; D020869:Gene Expression Profiling; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007124:Immunoenzyme Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008081:Liposomes; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000235:genetics / Q000517:prevention & control*; D009687:Nuclear Proteins / Q000502:physiology; D010641:Phenotype; D010750:Phosphoproteins / Q000502:physiology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000517:prevention & control*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D000071857:Tumor Suppressor p53-Binding Protein 1; D023041:Xenograft Model Antitumor Assays
D000727:Androgen-Binding Protein; C534699:CCNB1 protein, human; D002352:Carrier Proteins; C534700:Ccnb1 protein, mouse; D064199:Cdc20 Proteins; C577491:Cdc20 protein, mouse; D018797:Cell Cycle Proteins; D019926:Cyclin B; D056744:Cyclin B1; C092537:Ifi202b protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008081:Liposomes; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011944:Receptors, Androgen; D016160:Retinoblastoma Protein; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; C027519:probasin; C577488:CDC20 protein, human