title: Interleukin-6 inhibits the growth of prostate cancer xenografts in mice by the process of neuroendocrine differentiation.
abstract: In vitro, the human prostate cancer (PCA) cell line LNCaP can be permanently transdifferentiated into a quiescent neuroendocrine (NE) phenotype by the cytokine interleukin-6 (IL-6). Recently, we have shown that the growth of prostate cancer cells is significantly suppressed when cocultured with NE cells. In order to explore the inhibitory activity of IL-6 on prostate tumor growth, nude mice bearing xenografts of the PCA cell lines LNCaP and DU-145 (a line that is incapable of NE transdifferentiation by IL-6 in vitro) were treated with IL-6 for 3 weeks, either injected around the tumor or systematically released from implanted minipumps. Both administration forms of IL-6 inhibited the growth of LNCaP xenografts by more than 75% compared to the control group. In contrast, there was no difference in DU-145 tumor growth between IL-6-treated animals and controls. In comparison to control and DU-145 tumors, both IL-6 injected and pump-infused LNCaP tumors exhibited a significant increase in the expression of the NE markers neuron-specific enolase (NSE) and betaIII tubulin. Serum NSE levels were also significantly elevated in both IL-6-treated LNCaP tumor groups when compared to controls. IL-6 treatment resulted in G(0) cell cycle accumulation as evidenced by a loss of Ki-67 expression in > 90% of LNCaP tumor cells. These combined results demonstrate that IL-6-induced NE transdifferentiation of PCA cells has a significant inhibitory effect on tumor growth in mice. Agents, like IL-6, capable of NE transdifferentiation of PCA cells, should be considered as a new therapeutic approach for the treatment of prostate cancer.
authors.affiliation: Division of Medical Oncology, USC/ Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
authors.forename: Qingcai
authors.initials: Q
authors.lastname: Wang
authors.forename: Dimitris
authors.initials: D
authors.lastname: Horiatis
authors.forename: Jacek
authors.initials: J
authors.lastname: Pinski
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002454:Cell Differentiation / Q000187:drug effects*; D018450:Disease Progression; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009490:Neurosecretory Systems / Q000502:physiology; D010641:Phenotype; D010751:Phosphopyruvate Hydratase / Q000032:analysis; D011471:Prostatic Neoplasms / Q000503:physiopathology* / Q000662:veterinary; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D015850:Interleukin-6; D019394:Ki-67 Antigen; D010751:Phosphopyruvate Hydratase