title: Functional evidence implicating S100P in prostate cancer progression.
abstract: S100P protein regulates calcium signal transduction and mediates cytoskeletal interaction, protein phosphorylation and transcriptional control. We have previously shown how elevated S100P levels in prostate cancer strongly correlate with progression to metastatic disease. In our study, we evaluated the functional significance of S100P expression on prostate tumor growth in vitro and in vivo. S100P levels were modulated by overexpressing S100P in PC3 prostate cancer cells and by silencing S100P levels in 22Rv1 prostate cancer cells. Overexpression of S100P in PC3 cells promoted cell growth, increased the percentage of S-phase cells, decreased basal apoptosis rate and promoted anchorage independent growth in soft agar. Furthermore, prostate cancer cells overexpressing S100P were protected against camptothecin-induced apoptosis. Conversely, silencing of S100P in 22Rv1 cells using siRNA resulted in a prominent cytostatic effect. The influence of S100P on tumor growth and metastases were assessed in vivo. S100P-overexpressing PC3 cells had a dramatically increased tumor formation compared to controls. Microarray analysis showed the involvement of growth pathways including increased androgen receptor expression in S100P-overexpressing cells. These results provide the first functional proof that S100P overexpression can upregulate androgen receptor expression and thereby promote prostate cancer progression by increasing cell growth. Moreover, the results confirm the oncogenic nature of S100P in prostate cancer and suggest that the protein may directly confer resistance to chemotherapy. Hence, S100P could be considered a potential drug target or a chemosensitization target, and could also serve as a biomarker for aggressive, hormone-refractory and metastatic prostate cancer.
authors.affiliation: Pharmaceutical Genomics Division, The Translational Genomics Research Institute, Scottsdale, AZ.
authors.forename: Gargi D
authors.initials: GD
authors.lastname: Basu
authors.affiliation: Pharmaceutical Genomics Division, The Translational Genomics Research Institute, Scottsdale, AZ.
authors.forename: David O
authors.initials: DO
authors.lastname: Azorsa
authors.affiliation: Pharmaceutical Genomics Division, The Translational Genomics Research Institute, Scottsdale, AZ.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Kiefer
authors.affiliation: Pharmaceutical Genomics Division, The Translational Genomics Research Institute, Scottsdale, AZ.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Rojas
authors.affiliation: Pharmaceutical Genomics Division, The Translational Genomics Research Institute, Scottsdale, AZ.
authors.forename: Sukru
authors.initials: S
authors.lastname: Tuzmen
authors.affiliation: Pharmaceutical Genomics Division, The Translational Genomics Research Institute, Scottsdale, AZ.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Barrett
authors.affiliation: Genetic Basis of Human Disease Division, The Translational Genomics Research Institute, Phoenix, AZ.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Trent
authors.affiliation: Medical Biotechnology Center, VTT Technical Research Centre of Finland and University of Turku, Turku, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Kallioniemi
authors.affiliation: Pharmaceutical Genomics Division, The Translational Genomics Research Institute, Scottsdale, AZ.
authors.forename: Spyro
authors.initials: S
authors.lastname: Mousses
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D018450:Disease Progression; D015536:Down-Regulation; D017097:Electric Impedance; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011471:Prostatic Neoplasms / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D015854:Up-Regulation
chemical_list: D002135:Calcium-Binding Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; C103003:S100P protein, human